Idiopathic Pulmonary Fibrosis: Current Status, Recent Progress, and

Nov 14, 2016 - His scientific interests are centered on the design and synthesis of novel molecular entities as future therapeutics to address the ...
0 downloads 0 Views 3MB Size
Subscriber access provided by United Arab Emirates University | Libraries Deanship

Perspective

Idopathic Pulmonary Fibrosis: current status, recent progress and emerging targets. Yi-Min Liu, Kunal Nepali, and Jing-Ping Liou J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b00935 • Publication Date (Web): 14 Nov 2016 Downloaded from http://pubs.acs.org on November 14, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Revised Manuscript for Perspectives

Idiopathic Pulmonary Fibrosis: Current status, recent progress and emerging targets.

Yi-Min Liu,† Kunal Nepali,† Jing-Ping Liou*,†

School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.



School of Pharmacy, College of Pharmacy, Taipei Medical University.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 99

Abstract: Idiopathic pulmonary fibrosis (IPF), a chronic and progressive fibrosing interstitial pneumonia is a fatal lung disease with a median survival time of 3-5 years. Problems in accurate diagnosis, poor prognosis, limited clinical therapy and high mortality rate together demonstrate that the development of efficient therapeutic strategies for IPF is an important future endeavor. Deeper understanding of pathogenesis and identification of biomarkers and pathways involved might lead in the future to the emergence of some agents as novel therapeutics for IPF. This review article presents the pathogenesis, therapeutic interventions, treatment approaches, and strategies employed for the design of antifibrotic agents for the treatment of IPF along with the patent literature from the last 10 years. With a dozen antifibrotic agents with exciting preclinical potential in the armory, it seems certain that some of them will advance to clinical stage investigations. The results of clinical trials for some of the new agents are also awaited, to assess their benefits in terms of efficacy and survival benefits.

Keywords – idiopathic pulmonary fibrosis (IPF), lungs, biomarkers, kinases, pathogenesis, survival

ACS Paragon Plus Environment

Page 3 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1.

Journal of Medicinal Chemistry

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial pneumonia

of unknown cause characterized by worsening of dyspnea and lung function.1 IPF represents one of the major clinical problems of cystic fibrosis and chronic obstructive pulmonary disease 2. Despite being a rare disease, IPF is the most common and severe form of the idiopathic interstitial pneumonia (IIP) and is identified histologically as usual interstitial pneumonia (UIP) which is a form of lung disease characterized by progressive fibrosis of both lungs.1-4 IPF is a fatal lung disease with a median survival time between 3-5 years from diagnosis. Usually diagnosed with poor prognosis, the clinical course of IPF is highly variable. The annual incidence of IPF in the US has been estimated as 6.8-8.8 cases per 100,000 population using narrow case definitions and 16.3-17.4 per 100,000 population using broad case definitions. The prevalence of IPF in US was estimated between 14 - 27.9 cases per 100,000 population using narrow case definitions and between 42.7 - 63 cases using broad case definitions.5-6 Furthermore, the incidence of IPF is increasing year by year and recent analysis of IPF-related mortality data from the US indicates that the age-adjusted mortality rate has increased to 28.4% in men and 41.3% in women.7-8 In the UK, the status of IPF in terms of both incidence and mortality is close to that of the US.8-10 IPF is more common in men than in women and increases with age, particularly over the age of fifty.5-6,8 IPF is more frequently encountered in cigarette smokers, and the scenario does not improve even after smoking cessation.11 Other potential risk factors that have been described include

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 99

environmental exposures such as metal and wood dust, microbial agents, and gastroesophageal reflux.1-2,11 Recently, several studies have revealed that gene expression and epigenetic regulation have a significant connection to IPF.12-13 Diagnosis of IPF is quite difficult. Its symptoms are a dry cough, dyspnoea and clubbing of the tips of the fingers or toes.14 According to international clinical practice guidelines, the diagnosis of IPF requires consideration of a detailed clinical history of the patient. This requires a comprehensive investigation including environmental exposures and family history, the exclusion of other known causes of interstitial lung disease (ILD) such as connective tissue disease or drug toxicity and radiographic concordance. In some cases, a confirmatory diagnosis of IPF requires surgical lung biopsy. Overall, an accurate diagnosis of IPF needs to be accomplished by multidisciplinary discussion with experienced clinical experts in the field of ILD.1,15 On October 2014, the US Food and Drug Administration (FDA) approved two drugs for treatment of IPF, pirfenidone (1, Esbriet® ) and nintedanib (2, Ofev® ). Both the drugs reduced the progression of IPF and offered other survival benefits. However, no treatment is strongly recommended for patients with IPF.16 Problems in accurate diagnosis along with poor prognosis, limited clinical therapy and high mortality rate clearly demonstrate the need to develop efficient therapeutic strategies for IPF in the near future. This review article is basically focused on various aspects of IPF such as pathogenesis, therapeutic interventions and treatment approaches. Only two drugs have been approved for IPF, but

ACS Paragon Plus Environment

Page 5 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

medicinal chemists have made several attempts to design and evaluate new chemical architectures along with structural modifications of the existing approved agents. The present compilation also covers some selected interesting strategies employed for the design of antifibrotic agents and in the later sections, the patent literature for the last 10 years. The data presented can serve as a guide to a better understanding of the rare disease with an overview of the potent antifibrotics possessing significant to moderate antifibrotic activity. With a reasonable number of antifibrotic agents possessing exciting preclinical potential in the pipeline, it seems certain that some of them will advance to clinical stage investigations 2. Pathogenesis In recent years, there has been a transition in the concept of pathogenesis for IPF from an inflammatory-driven to an epithelial-driven disease. The former concept categorizes it as a chronic inflammatory disease associated with the interactions of mononuclear cells, fibroblasts and cytokines. However, more recently, new thoughts have been brought up and elucidated.4,17 IPF represents a form of abnormal wound healing involving the interstitial and alveolar spaces of the lung related to the excessive proliferation of myofibroblasts resulting in fibrosis (Fig 1). The inflammation is not the prime cause of the IPF, but it plays a significant role in the onset and progression of the disease.17-18 At first, the lung is repeatedly attacked by micro injuries such as cigarette smoking and viral infections on alveolar epithelial cells (AECs). These injuries lead to the death of epithelial cells and promote the wound healing process. Under normal conditions, the apoptosis of epithelial cells

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 99

initiates the wound healing process which enhances the vascular permeability to proteins (fibrinogen and fibronectin) and forms the wound clot. The damaged/dead cells are removed by the action of inflammation followed by the growth of fibroblasts forming a new extracellular matrix (ECM). After re-epithelialization, cells such as differentiated myofibroblasts which are involved in the wound healing process undergo apoptosis. In IPF, however, the abnormal wound healing responses lead to formation of fibroblast hyperplasia and exaggerated ECM deposition. This ultimately affects the balance between fibrotic mediators and anti-fibrotic mediators. The levels of active transforming growth factor β (TGF-β) are increased in patients with IPF. When this aberrant process is sustained, the repetitive lung remodeling eventually leads to the formation of honeycomb cysts and demolition of lung architecture ultimately causing progressive lung fibrosis along with loss of function.2,13,17-20

Figure 1. Pathogenesis and therapeutic targets of IPF

ACS Paragon Plus Environment

Page 7 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

3.

Journal of Medicinal Chemistry

Therapeutic targets Based on the pathogenesis of IPF, several therapeutic targets have been recognized and have led

to the development of anti-IPF agents. Some of these anti-IPF agents have already entered into clinical trials and are being marketed (Table 1). Table 1. Therapeutic intervention of IPF Mechanism of action Anti-fibrotic Antiinflammatory Anti-oxidant

Anti-PDGF receptors α/β; Anti-FGF receptors 1-3; Anti-VEGF receptors 1-3

Antioxidant; increases

Compound number, Evidence for antifibrotic name activity 1, Pirfenidone  Reduction of TGF-β70  Inhibition of proinflammatory cytokines73  Scavenger of hydroxyl radicals and superoxide anions74  Preserve vital capacity and improves progression-free survival time better than placebo in IPF patients with mild functional impairment without serious adverse events75  Reduction of disease progression in patients with IPF and the treatment was safe with an acceptable side-effect profile76-77 2, Nintedanib  Attenuation of fibrosis by the collagen deposition and inhibition of pro-fibrotic gene expression in rats90  Proliferation inhibition in primary human lung fibroblasts derived from patients with IPF91  Reduce decline in FVC with fewer acute exacerbations and preserve quality of life 94-95

Clinical Identifier trials FDA NCT02141087 approved (Marketed) Phase III NCT00287729 (Completed) NCT00287716 (CAPACITY) Phase III NCT01366209 (Completed) (ASCEND)

FDA approved (Marketed) Phase III (Completed) Phase III (Completed) Phase III (Activated)

NCT01335464 (INPULSIS-1) NCT01335477 (INPULSIS-2) NCT01619085 (INPULSISON) Phase II NCT00514683 (Completed) (TOMORROW)

3, N-acetylcysteine  No significant benefit with Phase III NCT00639496 respect to the preservation (Completed) (IFIGENIA)

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

cellular glutathione levels

BET bromodomain inhibitor

of forced vital capacity (FVC) in patients with IPF26-27  Addition of NAC to pirfenidone dose not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF28 4, JQ-1

Inhibiting the profibrotic effects of IPF lung fibroblasts and attenuates bleomycin-induced lung 30-31 fibrosis in mice

Histone 5, SAHA (Vorinostat) Promotes fibroblast deacetyltransfera apoptosis and ameliorates se inhibitor pulmonary fibrosis in preclinical study32 Anticoagulant

6, Warfarin

Direct thrombin 7, Dabigatran inhibitor

Direct factor Xa 8, Apixaban inhibitor

Page 8 of 99

Phase III NCT00650091 (Completed) (PANTHERIPF) Phase II NCT02707640 (Completed)

-

-

-

-

Increase deaths and Phase III NCT00957242 contribute to an underlying (Terminated) (ACE-IPF) worsening of respiratory status in patients with IPF40 Restrain important profibrotic events in lung fibroblasts and play as a potential antifibrotic drug for the treatment of IPF41

Increase local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury43

-

-

-

-

9, Rivaroxaban

Anti-IL-13 monoclonal

Tralokinumab (CAT354)

Attenuate lung fibrosis and Phase II NCT01629667 epithelial damage in a (Terminated)

ACS Paragon Plus Environment

Page 9 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

antibody

humanized mouse model of IPF47 QAX576

Phase I NCT01266135 (Terminated) Phase II NCT01872689 (Recruiting) Inhibit pulmonary fibrosis Phase II NCT01371305 and without exacerbating (Recruiting) inflammation 51 -

Lebrikizumab Anti-αvβ6 humanized monoclonal antibody

BG00011 (STX-100)

Anti-CTGF monoclonal antibody

FG-3019

Show safety and tolerability and demonstrate good outcomes in changes in pulmonary function and extent of pulmonary fibrosis54 Absence of PAR1 signaling could protect from bleomycin-induced lung fibrosis in animal study56 Inhibition of PAI-1 was shown to limit the development of bleomycin-induced lung fibrosis in mice59 Show the inhibition of lung fibrosis in the mouse bleomycin model62

PAR1 -

PAI-1 -

LPA1 antagonist 10, AM966

Nox4 inhibitor

BMS-986020 (Structure not disclosed) 11, 10-benzyl-2-(2chlorophenyl)2,3,3a,7,8,9,10,11octahydro-1Hpyrazolo[4',3':3,4]pyri do[1,2a][1,4]diazepine1,5(4H)-dione

Strongly abrogated lung fibrosis in preventive and curative murine model of bleomycin-induced pulmonary fibrosis118-119

ACS Paragon Plus Environment

Phase II NCT01890265 (Recruiting) Phase II NCT01262001 (Onoging) Phase I NCT00074698 (Completed)

-

-

-

-

-

-

Phase II NCT01766817 (Recruiting)

-

-

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 99

3.1 Epithelial cell injury. Apoptosis of epithelial cells can be attributed to repetitive micro injuries. The sources of injuries have not yet been confirmed and vary amongst patients, including for instance, environmental exposures or gastroesophageal reflux disease (GERD). Antioxidants and anti-reflux agents such as proton pump inhibitors (PPIs) or histamine-2 blocker receptor antagonists are probably the suitable therapeutics. Antacid medication as mentioned in the latest guideline is a conditional recommendation for use but with very low estimated confidence in its effects.16,21 Though the relationship remains unclear, up to 90% of patients with IPF have symptoms of gastroesophageal reflux. Retrospective studies have indicated the beneficial effects of PPIs together with good prognosis and extended survival. However, patients with long-term intake of PPIs should be aware of drug-drug interactions.21-23 There is ample evidence that the use of antioxidants improves the problem of high lung oxidant burden in IPF patients. However, the antioxidant 3, a precursor of the endogenous antioxidant glutathione, is not recommended for use of IPF.16 According to the Idiopathic Pulmonary Fibrosis International Group exploring N-Acetylcysteine I Annual (IFIGENIA) study, the addition of 3 to therapy with prednisone and azathioprine preserved vital capacity and better carbon monoxide

ACS Paragon Plus Environment

Page 11 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

diffusing capacity (DLCO) in patients with IPF but the results of the study had some potential limitations such as the lack of a true placebo arm due to the very high dropout rate. Moreover, there were no significant effects on survival. The study was therefore assumed either to underestimate or overestimate the effects of 3.24-25 Another study revealed the increased risks of death and hospitalization in patients with IPF who were treated with a combination of prednisone, azathioprine and 3.26 Compared to placebos, 3 offered no significant benefits with respect to the preservation of forced vital capacity (FVC).27 These investigations provide sufficient evidence against the use of this combination in IPF patients.24,26-27 Recently, a Phase II study has also suggested that addition of 3 to a pirfenidone administration does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF.28 Overall, the use of antioxidants as therapeutic strategy still needs exploration to ascertain conclusive benefits. Recently, accumulation of repeated micro injuries due to the cellular senescence associated with aging or telomere shortening has been reported. Aging is related to alteration of DNA methylation and histone modification which in turn is connected to epigenetic modifications.12 Several preclinical studies have already indicated that IPF is related to epigenetic modifications such as upregulation of histone deacetylase (HDAC) or enhancement of bromodomain proteins.29-32 According to Tang et al., 4 , a Brd4 inhibitor, is capable of inhibiting the profibrotic effects of IPF lung fibroblasts and attenuates bleomycin-induced lung fibrosis in mice.30-31 The results of the preclinical investigation conducted by Sanders et al indicates that SAHA (5, Vorinostat, Zolinza® ), an approved HDAC

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 99

inhibitor, promotes fibroblast apoptosis and ameliorates pulmonary fibrosis.32 Primary mutations of TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component) leads to short telomere lengths and telomere shortening of circulating leukocytes has been proposed as a marker of an increased predisposition toward the development of this age-associated disease.33 A common polymorphism in the promoter of MUC5B gene, which is upregulated two-digit times higher in the patients with IPF, has also been identified as a risk with strong associations with development of this chronic progressive parenchymal lung disease.34-35 Though the studies evaluating the effects of gene expression alteration and epigenetic modification are still at the preclinical stages, they hold enough promise and optimism as a new strategy for the treatment of IPF. 3.2 Early phase of wound healing. Normally, wound healing can be divided into four phases, blood clotting (hemostasis), inflammation, tissue proliferation and tissue remodeling. At the beginning of the blood clotting phase, vascular permeability increases and extravascular coagulation is induced by clotting factors. The balance between thrombus formation and fibrinolysis determines the vessel occlusion or bleeding.36-37 The prothrombotic state is four times higher in patients with IPF and the existence of a prothrombotic state has an adverse impact on survival due to a combination of inherited and acquired defects in the clotting cascade.38 The use of the traditional anticoagulant, warfarin (6), has been terminated due to increased deaths in the warfarin arm at interim analysis in the Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF) trial.39 Other studies also suggested that anticoagulants may contribute to an underlying deterioration of respiratory status

ACS Paragon Plus Environment

Page 13 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

in patients with IPF.40 Despite these unfavorable reports, two new groups of oral anticoagulants have been found to possess not only anticoagulant effects but also anti-fibrotic effects. One group is direct thrombin inhibitors, such as dabigatran (7), and the other is direct factor Xa inhibitors such as apixaban (8) and rivaroxaban (9). Thus, it is still hoped that these groups may provide a whole new anticoagulant therapeutic strategy in the near future.37, 41-43 3.3 Immune activation. The second phase of wound healing is inflammation, characterized by the sequential infiltration of neutrophils, macrophages and lymphocytes. Macrophages can release cytokines to promote the inflammatory response and remove the apoptotic, or damaged cells. The macrophages then secrete large amounts of growth factors such as TGF-β, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) to promote fibrosis.18-19 In addition, connective tissue growth factor (CTGF) is an important downstream mediator of TGF-β and inhibition of CTGF in the lungs has the potential to reverse tissue remodeling and the process of fibrosis.44-45 Interleukin13 (IL-13) released by T helper 2 (TH2) cells can also promote proliferation of fibroblasts.46 IL-13 monoclonal antibodies such as CAT354 can attenuate lung fibrosis and epithelial damage in a humanized mouse model of IPF.47 Two Phase II trials of the anti-IL-13 antibodies, CAT354 and QAX576, have been terminated for reasons that have not been disclosed, and lebrikizumab is currently recruiting participants for a Phase II, randomized, double-blind, placebo-controlled trial.48 All these factors have been found to be expressed in high levels in patients with IPF and consequently, inhibition of these factors presents a logical therapeutic approach for IPF.49

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 99

Historically, due to their anti-inflammatory effects, corticosteroids, especially prednisone have been used for treatment of IPF. However, the results of IFIGENIA and PANTHER-IPF studies investigating effects of the combination of prednisone, azathioprine and 3 have produced discouraging outcomes.24-26 Moreover the anticipated beneficial effects of corticosteroids have not been demonstrated by other studies and current recommendations are against the use of immunosuppressants in IPF.16,50 The αvβ6 integrin which is required for the activation of latent TGF-β is elevated in fibrotic diseases, and partial inhibition of αvβ6 integrin can inhibit pulmonary fibrosis without exacerbating inflammation.51-52 BG00011 (STX-100), a humanized monoclonal antibody against αvβ6, has recently entered into a Phase II clinical trial for the treatment of IPF.53 FG-3019, an anti-CTGF monoclonal antibody has been reported to be safe and well-tolerated for 45 weeks in IPF patients participating in the open-label Phase II trial. The clinical study demonstrated favorable outcomes in the context of changes in pulmonary function and extent of pulmonary fibrosis.54 3.4 Tissue proliferation. After the inflammation, the wound healing process enters the proliferative phase where proliferation of fibroblasts and angiogenesis is initiated. In IPF, the myofibroblasts which differ from fibroblasts, accumulate predominantly into the injuries, producing collagen and ECM components. In this period, some profibrotic mediators also provide a mechanistic link to prolongation of fibrosis. Thus, despite an accomplished repair process, the condition of abnormal fibrosis remains.

ACS Paragon Plus Environment

Page 15 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

PAR1 (proteinase-Activated Receptors) possess a potent fibrogenic effect which includes promotion of PDGF-mediated fibroblast proliferation and increased collagen synthesis.55 An animal study also indicated that absence of PAR1 signaling can lead to protection from bleomycin-induced lung fibrosis.56 PAI-1 (plasminogen activator inhibitor-1) is a potent downstream effector of TGF-β in fibrotic processes and plays an important role in the regulation of ECM degradation.57-58 Inhibition of PAI-1 has been reported to limit the development of bleomycin-induced lung fibrosis in mice.59 Both targets could emerge in future effective therapeutic interventions for the treatment of IPF. Fibroblasts, the most targeted cells, are considered to be an evaluation standard for potential treatments of IPF. To date, two drugs, pirfenidone (1) and nintedanib (2), approved for the treatment of IPF, also target fibroblasts and are discussed in detail in the next section. Apart from this, lysophosphatidic acid (LPA) and its specific G protein-coupled receptor (LPA1) can mediate fibroblast recruitment and apoptosis through LPA-LPA1 signaling.60-61 Compound 10, a novel, orally active potent LPA1 antagonist inhibits lung fibrosis in the mouse bleomycin model and another structurally related compound, BMS-986020 (structure not disclosed) has recently entered into Phase II clinical trial for the treatment of IPF.62-64

4. Treatment approaches The treatment of IPF can involve either of two different approaches, pharmacological therapy and non-pharmacologic therapy. The treatment of concomitant conditions of IPF is also another

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 99

important subject that must be addressed. Currently, only two drugs, pirfenidone and nintedanib have been approved by U.S. Food and Drug Administration (FDA) for treatment of IPF.65 4.1 Pirfenidone Pirfenidone (1) is an orally available pyridone derivative (5-methyl-1-phenyl-1H-pyridin-2-one) that has been licensed in numerous countries including Japan, India, China, Europe, Canada and the United States for the treatment of IPF. The approved dose is nine 267 mg capsules, for a total of 2403 mg, per day. The treatment should be used in a titration manner to the recommended daily dose over two weeks and taken with food to reduce the adverse gastrointestinal effects. Pirfenidone is predominantly metabolized by cytochrome P450 (CYP450) 1A2 enzyme and excreted renally. The elimination half-life of pirfenidone is about 3 h and its most frequent adverse effects include skin rashes, diarrhea and fatigue.66-67 Although the mode of action of pirfenidone has not yet been established, it possesses antifibrotic, anti-inflammatory and anti-oxidant potential.68-69 The anti-fibrotic properties of pirfenidone are attributed to its ability to reduce expression of cytokines such as TGF-β, resulting ultimately in inhibition of fibrosis.70-71 Pirfenidone exerts

anti-inflammatory effects via inhibition of pro-

inflammatory cytokines, for instance the IL-6, IL-8 and tumor necrosis factor (TNF)-α, as well as enhancement of the anti-inflammatory cytokine IL-10.72-73 Pirfenidone is ineffective as a scavenger of superoxide radicals but is a scavenger of hydroxyl radicals and superoxide anions, indicating its anti-oxidant properties.74

ACS Paragon Plus Environment

Page 17 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Four Phase III clinical studies of pirfenidone in IPF have been completed and reported.75-77 A study conducted in Japan demonstrated that pirfenidone preserves vital capacity and improves progression-free survival time without serious adverse events and better than a placebo in IPF patients with mild functional impairment.75 The CAPACITY (Clinical Studies assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcome) studies included two randomized trials (studies 004 and 006) which demonstrated clinical benefits along with a favorable safety profile of pirfenidone. Overall, the study presented a suitable treatment option for patients with IPF.76 Another Phase III trial, ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) study, also confirmed that pirfenidone reduces disease progression in patients with IPF and that the treatment is safe compared with placebo with an acceptable side-effect profile.77 4.2 Nintedanib Nintedanib (2), formerly known as BIBF1120, is an indolinone derivative that was identified in a lead optimization program designed for angiogenesis inhibitors with anti-cancer effects. Nintedanib is a potent and orally available triple tyrosine kinase inhibitor that targets the PDGF receptors α/β, FGF receptors 1 to 3, and all three vascular endothelial growth factor (VEGF) receptor subtypes.78-79 The approved dose of nintedanib is 300 mg/day and each capsule contains 150 mg. The appropriate dosage regimen recommends 150 mg of nintedanib to be taken orally (with food) twice daily approximately 12 h apart. Nintedanib is predominantly metabolized by the CYP450 enzymes via

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 99

ester cleavage and oxidative N-demethylation. It is mainly excreted in the bile. The elimination halflife of nintedanib is about 9.5 h and the common adverse effects of nintedanib are diarrhea, nausea and abdominal pain.80-81 PDGFs are expressed in many types of cells including fibroblasts, vascular endothelial cells, macrophages and platelets. PDGFs can induce fibroblast chemotaxis and are the strongest stimulus of fibroblast proliferation. They therefore play an important role in the expansion of myofibroblasts and act as a stimulator of collagen synthesis.82-84 PDGF inhibitors such as imatinib have been reported to alter fibrogenic response thereby reducing pulmonary fibrosis in animal studies.85-86 The FGF pathway is an essential signaling pathway controlling angiogenesis, morphogenesis and remodeling in the airway. Specifically, FGFR-1 and -2 are expressed in myofibroblast-like cells.87 Although VEGF signaling is prominent in vascular remodeling, the relationship between VEGF and IPF has not yet been established.88 However, there are reports that with bleomycin-induced fibrosis in mice, a VEGFR-2 antagonist could attenuate histopathologic fibroplasias and collagen deposition by regulating angiogenesis and inflammation in the lung.89 Thus, the signaling of PDGF, FGF and VEGF has emerged as an logical therapeutic target of IPF. Methyl (Z)-3-(((4-(2-(dimethylamino)-Nmethylacetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate

(BIBF1000),

a

small molecule inhibitor targeting PDGF, FGF and VEGF, has attenuated fibrosis by reducing collagen deposition and inhibiting pro-fibrotic gene expression in rats.90 Nintedanib has demonstrated significant anti-fibrotic effects by inhibition of proliferation in primary human lung

ACS Paragon Plus Environment

Page 19 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

fibroblasts derived from patients with IPF.91 Nintedanib has been investigated in Phase II and Phase III clinical trials.92-93 The randomized, double-blind, placebo-controlled, Phase II trial, also known as the TOMORROW trial suggested that treatment with 150 mg of nintedanib twice per day resulted in reduced decline in FVC, with fewer acute exacerbations and preserved quality of life compared with a placebo.94 In the two replicate Phase III trials, the INPULSIS-1 and INPULSIS-2, the primary outcome was achieved, with an approximately 50% reduction in the annual rate of FVC decline in the nintedanib group compared to placebo. This was found to be consistent with a slowing of the disease progression. The most frequently encountered adverse event was diarrhea reported in 62% of patients. However less than 5% of nintedanib-treated patients discontinued the trial.95 The INPULSIS-ON trial, an open-label extension of the INPULSIS trials, has confirmed the long-term efficacy and safety of nintedanib in an interim analysis.96

5.

Rational approaches, design strategies, structure activity relationship of antifibrotic

agents This section presents the rational approaches and design strategies employed by researchers to synthesize antifibrotic agents for IPF. The structure activity relationships and the key interactions revealed from the molecular modeling studies and the key findings of the pharmacological evaluation are also discussed.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

5.1

Page 20 of 99

Pyrazolo-pyrido-diazepine, -pyrazine and -oxazinedione derivatives as novel dual

Nox4/Nox1 inhibitors There is much evidence that NADPH oxidase isoform 4 (Nox4) is the key source of reactive oxygen species (ROS) in the pathogenesis of idiopathic pulmonary fibrosis. Nox4 has also been found to be upregulated in mouse models of IPF and in lung fibroblasts of human IPF patients. Abrogation of fibrogenesis in bleomycin-induced/FITC-induced models of lung injury via genetic or pharmacologic silencing has also been reported.97 Keeping in view the role of Nox4 in tissue fibrogenesis and therapeutic benefits of targeting Nox4 in fibrotic disorders, a group of researchers led by Patrick Page identified pyrazolopyridine diones as a first in class, potent, and orally bioavailable Nox4 inhibitors. The most potent molecule displayed significant efficacy in in vitro assays on human fibroblasts differentiation, epithelial cells apoptosis and epithelial-mesenchymal transition. It also exhibited remarkable benefits in preventive and curative murine models of bleomycin-induced pulmonary fibrosis. In extension of this work, pyrazolo-pyrido-diazepine dione derivatives were designed and synthesized by same group.98 Among the compounds synthesized, 12 (Ki Nox1 = 101 ± 10 nM, Ki Nox4 = 72 ± 3 nM) (Fig. 2) exhibited high potency in the in vitro assays of human lung fibroblast differentiation as well as in curative murine models of bleomycininduced pulmonary fibrosis. Compound 12 was found to be endowed with efficiency superior than that of pirfenidone. It exhibited a good compromise between microsomal metabolism, free fraction, permeability, and physical properties associated with high Nox4/Nox1 potency and the highest

ACS Paragon Plus Environment

Page 21 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Nox4/Nox2 selectivity ratio (18.6). The pharmacokinetic profiling of 12 was also very exciting with high exposure owing to its good physicochemical properties and higher permeability. A counter screening assay for potential ROS scavenging was performed to evaluate the Nox specificity of 12. The results indicated no potential problem regarding CYP450 inhibition and also revealed that 12 was not mutagenic or genotoxic. Lung fibrosis was strongly abrogated by 12 following once daily oral administration from days 10 to 25 after bleomycin intratracheal administration in a curative model of bleomycin-induced pulmonary fibrosis. Compound 12 (10 mg/kg p.o.) inhibited the collagen deposition by 64% at this dose as compared to only 12% inhibition by pirfenidone (100 mg/kg p.o.). The study concluded that 12 possesses an excellent pharmacological and safety profile with Ki in the two digit nanomolar range on Nox4 and deserves to be investigated clinically for the treatment of idiopathic pulmonary fibrosis.98

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 99

Figure 2. Pyrazolo-pyrido-diazepine, -pyrazine and -oxazinedione derivatives as novel dual Nox4/Nox1 inhibitors 5.2

Novel pirfenidone analogues for the treatment of pulmonary fibrosis Motivated by the ability of pirfenidone, administered at 0.5% (w/w) of the diet to decrease the

biochemical evidence of lung fibrosis in a variety of animal models99-103, a series of polysubstituted 1-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles,

pyrazolo[3,4-b]pyridine-5-carbonitriles

and

pyrido[2,3-d]pyrimidine-6-carbonitriles (Fig. 3) were synthesized and their antifibrotic activity was evaluated.104 Among the compounds synthesized, 13 and 14 displayed promising antifibrotic potential. For the biological evaluation, the lung content of hydroxyproline (HP) was determined as a biochemical index of fibrosis. Compound 13 (HP = 48.55 μmol/lung) with a 4-ethoxyphenyl group

ACS Paragon Plus Environment

Page 23 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(at the 1 position) was the most potent compound when compared to pirfenidone (HP = 158.39 μmol/lung). The biochemical evidence was well supported by a histopathological study. The positive influence of the electron releasing group on the activity was further confirmed by the drastic decline in the antifibrotic potential of another analogue possessing the 4-fluorophenyl group. The decline in antifibrotic potential was attributed to the electron withdrawing property of fluorine which was assumed to increase the hypoxanthine level. A similar trend was observed with 14 which was also endowed with impressive antifibrotic activity. Significant activity of 14 (HP = 119.55 μmol/lung) compared to that of the pirfenidone group was attributed to the electron releasing effect of the substituents conferring a higher antifibrotic activity. Compounds 13 and 14 showed remarkable decreases in the lactate dehydrogenase (LDH) activity levels. Compound 14 normalized the protein content whereas 13 led to no noticeable change in the protein concentration.104

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 99

Figure 3. Novel pirfenidone analogues for the treatment of pulmonary fibrosis 5.3 Pirfenidone derivatives as antifibrotic agents The reduced bioactivity owing to the fast metabolism of pirfenidone in the human body has motivated researchers to modify pirfenidone structurally with the aim of increasing its half-time and antifibrotic activity.105-109 With this background, a group of researchers led by Zhengrong Shen designed and synthesized pirfenidone derivatives and evaluated the influence of different side chains on their antifibrotic potency. The design strategy involved introduction of a side chain with a 4alkoxylphenyl group including a terminal amine to the 1-position of a pyridone scaffold, and varying the length of the linker between the scaffold and the amine and selection of different amines to

ACS Paragon Plus Environment

Page 25 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

determine the influence of hydrophobicity on the biological activity. Twenty four pirfenidone derivatives were synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. All the synthesized compounds exhibited significant inhibitory potential against MRC-5 compared to pirfenidone which possessed the IC50 value of 14.4 mM. Compound 15 exhibited the most potent inhibitory potential against MRC-5 cell line (10 folds more potent than pirfenidone) with an IC50 value of 1.36 mM. The association of fibrogenesis with inflammation is well evidenced with TNF-α and TGF-β being the two major molecules for tissue fibrosis. TNF-α and TGF-β play vital roles in the induction of fibrosis. p38, a member of the stress activated protein kinase family also has a key role in the mediation of inflammatory response and tissue remodeling. Thus molecular docking studies of 16 were performed with p38, TNF-α and TGF-β using the Discovery Studio 2.1/Flexible Docking protocol on a model structure (PDB ID:3HP2, 1QSC and 3FAA). The results of the docking study revealed that 16 was well stabilized within the active site of p38 by hydrogen bonding interactions. Such interactions were not observed with the amino acid residues of TNF-α and TGF-β and thus 16 appeared more likely to be the ligand of p38. Rationalization of the computational study was carried out and the synthesized compounds were evaluated for their binding activity with p38 in vitro. In the assay, (IC50 = 4.07 μM) was found to be 40-fold more potent than pirfenidone (IC50 = 165.40 μM). Overall the study concluded that three or four methylenes between scaffold and amine, and heterocyclic amines might be beneficial for inhibitory activity against p38. The results indicated strongly the induction of antifibrotic effects by

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 99

the synthesized compounds via the p38 MAPK pathway. Thus p38 could be the possible target for the design of new antifibrotics (Fig. 4).110

Figure 4. Pirfenidone derivatives as antifibrotic agents 5.4 Pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A Several reports indicated that pulmonary fibrosis possesses a similar pathological basis as lung cancer mediated by growth factors.111 It is well-known that pulmonary fibrosis is associated with an increased risk of lung cancer.112-113 With this background, pyridin-2(1H)-ones with different substituents at the N-1 position and C-5 position of pyridin-2(1H)-one scaffold were designed. The

ACS Paragon Plus Environment

Page 27 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

design included a study of structure-selectivity relationships (SSR) and structure activity relationships together with mechanistic studies. A series of synthetic, 1,5-disubstituted-pyridin2(1H)-one derivatives were tested for anticancer and antifibrosis effects. For the evaluation, A549 (human lung adenocarcinoma cell with high expression of eIF3a), and NIH3T3 (a mouse embryonic fibroblast cell line with low expression of eIF3a) cell viability assays were employed. Among the synthesized compounds, exciting results were observed with 17 which exhibited both potency and selectivity (IC50 = 0.13 mM) for the A549 cell line via inhibition of translation initiation (eIF3a suppression-biomarker for lung cancer). The study proposed 17 as a lead compound with which to construct novel scaffolds as eIF3a regulators and anti-lung cancer agents. Compound 18 (IC50 = 0.016 mM) and 19 (IC50 = 0.014 mM) exhibited significant antifibrotic potential against NIH3T3 cell proliferation (Fig. 5)114.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 99

Figure 5. Pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A

5.5. Carbohydrate-modified 1-(Substituted aryl)-5-trifluoromethyl-2(1H) pyridones as antifibrotic agents With the objective of preparing antifibrotics with greater water solubility and improved pharmacokinetics, carbohydrate modified 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones were designed and synthesized by Lou et al.108, 115 Fluorofenidone, [1-(3-fluorophenyl)-5-methyl-2(1H)-pyridone], a small molecule compound structurally related to perfinedone with antiinflammatory and anti-fibrotic properties was employed as a standard. Promising results were

ACS Paragon Plus Environment

Page 29 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

observed with most of the compounds whose inhibitory activity was comparable or better than that of fluorofenidone. Compound 20 (IC50 = 0.17 mM), for example, exhibited remarkable inhibitory potential against NIH3T3 cells and was the most potent of the synthesized compounds. The results of the biological evaluation highlighted the key structural features essential for potent inhibition of NIH3T3 cells. Glucose appeared to be the preferred carbohydrate among those tested. The positioning of the amine on the chemical architecture of the designed compounds was crucial for activity with the amine functionality preferred at the ortho position. A methylene group linkage between the substituted phenyl ring and 5-trifluoromethyl-2(1H)-pyridone resulted in potent compounds and this was attributed to the increased flexibility between two substituted aryl rings (Fig. 6). Overall the study indicated that modifications of pirfenidone analogues with carbohydrates potentiate the inhibitory activity against NIH3T3 cell proliferation.108

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 99

Figure 6. Carbohydrate-modified 1-(Substituted aryl)-5-trifluoromethyl-2(1H) pyridones as antifibrotic agents

5.6 5-substituted 2(1H)-pyridone derivatives as antifibrotic agents Pirfenidone and fluorofenidone, are multi-target antifibrotic agents which act on TNF-α, TGF-β, PDGF, and NF-κB. Despite their remarkable efficacy for the treatment of lung fibrosis, both the drugs possess some limitations, including short half-life, low efficacy and requirement of high doses.115-119 With the objective of overcoming these shortcomings while retaining the multitargeting potential, two series of novel 5-substituted-2(1H)-pyridone compounds were synthesized by Chen et

ACS Paragon Plus Environment

Page 31 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

al. A total of 31 novel pyridine derivatives were synthesized and tested against NIH3T3 cell proliferation using an MTT assay. Pirfenidone and fluorofenidone were employed as positive controls. The synthesized compounds were found to have good inhibitory effects against NIH3T3 cells with 21 being the most potent with IC50 = 0.08 mM, 34 times that of fluorofenidone (IC50 = 2.75 mM). Some details of the structure–activity relationships emerged from the results of the biological evaluation (Fig. 7).120

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 99

Figure 7. 5-substituted-2(1H)-pyridone derivatives as anti-fibrotic agents

5.7 N1-Substituted phenylhydroquinolinone derivatives with antifibrosis activity In view of the requirement of high doses of pirfenidone for antifibrosis activity115-119, N1substituted phenylhydroquinolinone derivatives retaining the 1-phenyl-2(1H)-pyridone scaffold were designed and synthesized in the hope of maintaining the multitargeting potential. The design strategy

ACS Paragon Plus Environment

Page 33 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

involved a) cyclization through C-5 and C-6 to form the phenylhydroquinolinone scaffold to prevent the rapid metabolism of the 5-CH3 b) placement of hydrogen bond donors or acceptors at C-5 of hydroquinolinones c) introduction of different substituents on the N-1 phenyl group. The designed compounds were synthesized and evaluated against NIH3T3 cell lines using an MTT assay. Significant inhibition of NIH3T3 cell proliferation was exhibited by the compounds (IC50 = 0.09–26 mM). Compound 22 with IC50 = 0.3 mM exhibited 14 times higher potency than that of fluorofenidone (IC50 = 4.2 mM). Compound 23 (IC50 = 0.09 mM) exhibited potency 46 times higher than that of fluorofenidone. Structure activity relationship studies revealed that the presence of a hydrogen bond donor on C-5 of the hydroquinolinones and aromatization of tetrahydroquinolin2(1H)-one to dihydroquinolin-2(1H)-one proved beneficial to the antifibrotic activity. The study proposed N1-substituted phenylhydroquinolinone as a promising scaffold for the development of novel antifibrotic agents (Fig. 8).107

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 99

Figure 8. N1-substituted phenylhydroquinolinone derivatives with anti-fibrosis activity

5.8 1,5-Disubstituted pyridone derivatives as antifibrotic and anti-lung cancer agents In search of potent anti-lung cancer agents possessing antifibrotic potential, a series of 1,5disubstituted pyridone derivatives were designed and synthesized. The design strategy involved introduction of benzyl groups in place of phenyl group at N-1 of the pyridine moiety and placing of various substituents on the two aromatic rings. Compound 24 and 25, which were earlier reported to possess potency and selectivity against A549 and NIH3T3 cell lines were employed as leads.114 The

ACS Paragon Plus Environment

Page 35 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

designed molecules were synthesized and evaluated for their inhibitory effects against A549 and NIH3T3 cell lines. Among the synthesized compounds, 26 was found to be the most potent and selective towards A549 cell lines with IC50 = 20 µM in comparison to cisplatin (IC50 = 10 µM). The inhibitory activity of 26 was found to be superior to that of the lead compound (25). NIH3T3 cells were also found to be sensitive to exposure to 26 (IC50 = 55 µM). Compound 27 exhibited remarkable antifibrotic potential with IC50 = 3 µM, almost 151 fold higher than that of pirfenidone (IC50 = 454 μM). 3D-QSAR models based on the activity data indicated the need for further studies on promising anti-lung cancer agents with antifibrotic effects (Fig. 9).121

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 99

Figure 9. 1,5-disubstituted pyridone derivatives as antifibrotic and anti-lung cancer agents

5.9 5-ene amino/iminothiazolidinones as antifibrotic agents Evidence exists that superoxide anion radicals play an important role in fibrotic disorders. They activate fibroblasts to produce collagen and the profibrotic cytokine TGF-.122-123 With this background and anticipation of the advantages of the superoxide scavenging properties of anticancer and antifibrotic agents, a series of 5-ene amino/iminothiazolidinones was synthesized. A one pot multicomponent strategy involving [2 + 3] cyclocondensation and Knoevenagel condensation was

ACS Paragon Plus Environment

Page 37 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

employed for the synthesis of desired compounds. The formation of potentially reactive and electrophilic compounds by allowing Michael addition of nucleophilic protein residues to the exocyclic double bond as a result of the conjugation of the 5-ene fragment to the C4 carbonyl group of the thiazolidinones and the need for new drugs for the treatment of idiopathic pulmonary fibrosis basically

led

the

authors

to

explore

the

pharmacological

attributes

of

5-ene

amino/iminothiazolidinones. Michael acceptors are considered to be the most effective activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) which offers much scope for the treatment of inflammation and cancer.124 The results of a fibroblast viability assay (SRB assay) were promising because the compounds significantly reduced the viability of fibroblasts. However anticancer activity was not demonstrated by the compounds which possess significant antifibrotic activity. Compounds 28-31 (IC50 = 0.03 - 0.57 μM) were potent antifibrotics with activity profiles similar to that of pirfenidone (IC50 = 0.71 μM) (Fig. 10). However, these compounds failed to exhibit superoxide scavenging activity. The results of the study revealed thiazolidinone derivatives to be interesting candidates for the design of new chemical architectures as potent antifibrotics.125

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 99

Figure 10. 5-ene amino/iminothiazolidinones as antifibrotic agents

5.10 Lysophosphatidic acid receptor‑1 antagonists with potent activity on human lung fibroblasts LPA, a class of biologically active phospholipids produced from lysophosphatidyl choline (LPC) catalyzed by the enzyme autotaxin (ATX), exerts a wide range of cellular responses, such as calcium mobilization, cell proliferation, cell transformation, and chemotaxis through a family of membrane bound GPCRs.126 Recently an increase in the LPA levels in bronchoalveolar lavage fluid (BALF) following lung injury was seen in an in vivo model of murine bleomycin-induced pulmonary fibrosis. The results of this study indicated that blocking LPA1 signaling could be the basis of a logical strategy for the treatment of idiopathic pulmonary fibrosis.127 In view of this, pyrazole- and triazole-

ACS Paragon Plus Environment

Page 39 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

derived carbamates were designed as LPA1 selective and LPA1/3 dual antagonists in the anticipation that aminopyrazole or aminotriazole could function as bioisosteres of the aminoisoxazole in 3-((4-(4(((1-(2-chlorophenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)benzyl)thio)propanoic acid (Ki16425), and

2-(4'-(4-(((1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)acetic

acid

(AM095), previously reported LPA1 antagonists, respectively.128 The results of the study were exciting with 32 (LPA1, IC50 = 25.2 nM) as the most selective LPA1 antagonist (Fig. 11). Inhibition of proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation was induced by 32. A dose dependent reduction of plasma histamine levels in a murine LPA challenge model was observed with 32 orally administered to mice. Mediation of the pro-fibrotic responses by LPA1/2/3 was investigated and LPA1 was found to be the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF. Structure activity relationship studies indicated that a)

N-aryltriazoles were more selective for LPA1 than compounds from the

corresponding pyrazoles, b) substitution on the phenyl ring of the carbamate or replacement of the phenyl group with alkyl groups led to reduced antiproliferative potency, c) for the heterocyclic triazole core, deletion of the methyl group or substitution with an ethyl group on the triazole moiety was well tolerated, and d) N-aryl-[1,2,3]triazoles were more active than the N-aryl-[1,2,4]triazoles. This was attributed to conformational differences between the two heterocyclic systems due to unfavorable electronic repulsion in N-aryl-[1,2,4]triazoles.129

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 40 of 99

Figure 11. Lysophosphatidic acid receptor-1 antagonists

5.11. 5-Amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists Strong evidence of elevated LPA levels in BALF in patients with IPF and the identification of

ACS Paragon Plus Environment

Page 41 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

the LPA1R as the predominant LPA receptor in lung fibroblasts of IPF patients responsible for enhanced fibroblast cell migration together motivated researchers to design LPA1R antagonists as a potential therapeutic approach to treat IPF.127,128,130 The chemical library of LPA1R antagonists was subjected to high throughput screening (HTS) which led to the identification of 33 as a potent antagonist of the LPA1 receptor (Fig. 12). Detailed investigation of this compound revealed that a degradation product of 33 was responsible for the LPA1R antagonist activity. Sidduri et al isolated and characterized the degradation products and this was followed by evaluation of their LPA1R antagonist activity. Several analogues were synthesized using the one-pot Groebke–Blackburn– Bienaymé reaction and bicyclic heterocycles were constructed. Compounds 33-35 were the most potent among those tested (Fig. 12). The results of the investigation demonstrated the inhibition of LPA-induced proliferation and contraction of NHLF by non-carboxylic acid LPA1R antagonists.131

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 42 of 99

Figure 12. 5-Amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists

5.12 Protein kinase inhibitors in the treatment of Pulmonary Fibrosis The emergence of apoptosis resistant myofibroblasts following activation of the protein kinase pathways and the ability of protein kinase inhibitors to target pro-survival signaling for the treatment of pulmonary fibrosis highlighted their potential as interesting antifibrotic agents.132 The structures of selected protein kinase inhibitors with antifibrotic properties are shown in Fig.13. Imatinib mesylate, an inhibitor of the Abl protein tyrosine kinase was found to be effective in the murine

ACS Paragon Plus Environment

Page 43 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

model of bleomycin-induced pulmonary fibrosis. However the results were not very consistent and this could be due to the difference in dosage regimen or the genetic background of the mice.133 Rapamycin, a natural product of the soil bacterium, Streptomyces hygroscopicus, inhibits mTOR, a mammalian homolog of target of rapamycin and also the proliferation of mesenchymal cells. In the murine model of bleomycin induced pulmonary fibrosis, it exhibited the potential to protect against fibrogenesis.134 Compound 36 (GW6604) and 37 (SB-525334)

represent the kinase inhibitors

targeting the TGF-β receptor I with antifibrotic activity in IPF.135 Compound 38 (AG1879), a SRC kinase-specific inhibitor, inhibits activation of FAK and AKT. It also reduces the accumulation of myofibroblasts in association with abrogated fibrotic responses to lung injury.136 Compound 39 (EW7197) , a novel ALK-5 kinase inhibitor has also exhibited strong potential as an antifibrotic therapeutic agent for pulmonary fibrosis by inhibition of TGF-β/Smad2/3 and ROS signaling (Fig.13).137

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 44 of 99

Figure 13. Protein kinase inhibitors with antifibrotic effects A clear understanding of structural requirements for c-Jun N-terminal kinase (JNK) potency along with kinase selectivity138 enabled the group of researchers to perform optimization of a diaminopurine series as a new class of JNK inhibitors. In an attempt to improve the physicochemical properties and increase the potency and selectivity, 40 (CC-930) was identified as an orally active antifibrotic JNK inhibitor. This compound has favorable physicochemical properties and was found to be kinetically competitive with ATP in the JNK-dependent phosphorylation of the protein substrate c-Jun and potent against all isoforms of JNK (Ki (JNK1) = 44 ± 3 nM, IC50 (JNK1) = 61 nM, Ki (JNK2) = 6.2 ± 0.6 nM, IC50 (JNK2) = 5 nM, IC50 (JNK3) = 5 nM). It also displayed selectivity against MAP kinases ERK1 and p38a with IC50 values of 0.48 and 3.4 μM, respectively (Fig. 14).139

ACS Paragon Plus Environment

Page 45 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

A preliminary investigation in healthy male volunteers demonstrated that 40 is well-tolerated and the exposure is dose-proportional.140 A Phase II clinical trial of 40 in patients with IPF began in January 2010 but terminated in 2013 due to the benefit and risk profile.141 However, 40 is currently being clinically evaluated for lung fibrosis.

Figure 14.40, an orally active antifibrotic JNK inhibitor

A lead optimization study on 41 led to the development of 42 (AX13587) as a JNK inhibitor.142 Docking studies were performed to identify key molecular interactions with JNK1. The results of kinase profiling indicated promising results as 42 was found to significantly inhibit JNK, MAST3, and MAST4. The methylene homolog of 42, 43 (AX14373) (native JNK1 IC50= 47 nM) was reported to be a highly specific JNK inhibitor (Fig. 15).143 With these promising results, it can be anticipated that 43 may possess significant potential for the treatment of IPF as the other JNK inhibitor.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 46 of 99

Figure 15. 42 as a JNK inhibitor

The involvement of TGF-β1, a fibrogenic cytokine, in the pathogenesis of pulmonary fibrosis by regulation of extracellular matrix deposition in the response to lung tissue injury has been well reported. TNF-α is an important pro-inflammatory cytokine which is involved in regulation of the inflammation in response to lung tissue injury.144 Motivated by the clinical promise of ivacaftor in pulmonary fibrosis, along with the well-evidenced role of cytokines in the pathogenesis of this chronic progressive parenchymal lung disease, several 4-oxoquinoline-3-carboxamide derivatives

ACS Paragon Plus Environment

Page 47 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

were synthesized by Zhu et al. employing ivacaftor as the lead. Among the synthetic derivatives, 4446 displayed potent inhibitory potential of both TGF-β1-induced total collagen accumulation and lipopolysaccharides (LPS)-stimulated TNF-α production. Compound 45 at 20 mg/kg/day, administered orally for 4 weeks, remarkably attenuated lung inflammation and injury. It was also found to decrease the lung collagen accumulation in a bleomycin-induced pulmonary fibrosis model. The results of the investigation demonstrated the promise of 45 as a potential, orally active antifibrotic agent for pulmonary fibrosis (Fig. 16).145

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 48 of 99

Figure 16. 4-oxoquinoline-3-carboxamides derivatives as potent antifibrosis agents for pulmonary fibrosis

6.

Patent literature This section presents the structures of the compounds patented since 2006 for the treatment of

IPF. In 2016, Schwiebert et al. filed a patent on various coumarin derivatives for the treatment of IPF. Of all the synthesized coumarin derivatives, seven coumarin compounds were tested with varied dosages from 0.001 to 100 µM and subsequent inhibition of fibrosis growth was determined. Among

ACS Paragon Plus Environment

Page 49 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

all the tested compounds, 47 exhibited significant growth inhibitory effect with GI50 = 0.19 µM (Fig. 17).146 In 2016, Gilbert et al. published a patent on dihydropyrimidinoisoquionolinones for the treatment of an inflammatory condition i.e. IPF. The preparation and evaluation of the compounds was reported. The compounds were found to antagonize the GPR84, a G-protein coupled receptor that is indirectly involved in this inflammatory disease. All the compounds were evaluated by in vitro as well as in vivo methods. Compounds 48-55 were found to be most potent, exhibiting IC50 values ranging from 0.01 to 100 µM. The solubility and the pharmacokinetic profile of the compounds were also determined and the results indicated that the compounds could be administered through different routes depending on their formulation (Fig. 17).147

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 50 of 99

Figure 17. Patented compounds (47-55) for the treatment of IPF

Josef et al. filed a patent in 2015 for the synthesis and evaluation of various derivatives of methylpyrrolopyrimidinecarboxamides for the treatment of IPF. All the compounds significantly inhibited the enzyme phosphodiesterase 4 and 5 (PDE-4, 5), an enzyme that leads to drastic inflammatory conditions, specifically IPF. Most of the compounds exhibited a -log IC50 value ranging from 8 to 9 mol-1 against PDE-5 and 6 to 7 mol-1 against PDE-4. Pharmacological evaluation of the compounds in animals was carried out against both the enzymes using Sprague Dawley rats. All the compounds tested were administered orally. In this model changes to the arterial vascular response and the PDE-5 activity were assessed. The percentage change vs. control was found to be approximately between -11% to -40% for compounds 56-60. Similarly, pharmacological testing was done for PDE-4. On the other hand, the compounds were tested for inhibition of LPS-induced TNF-α production in male Sprague Dawley rats. The inhibition of LPS in this model achieved by the compounds 61-65 was between 7 and 99%. These active molecules thus could be used to treat the inflammatory condition, IPF (Fig. 18).148

ACS Paragon Plus Environment

Page 51 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Figure 18. Patented compounds (56-65) for the treatment of IPF John et al. filed a patent in 2015 on various analogues of 1H-pyrazolo[3,4-b]pyridines for the treatment of IPF. The Wnt/β-catenin pathway is implicated in the etiology of this disease and it was postulated that the β-catenin is over-expressed in epithelial cells, increasing the presence of proliferating fibroblasts which leads to excess collagen deposition in the lungs, a pathological

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 52 of 99

hallmark of IPF. The synthesized compounds were screened in a β-catenin based receptor assay in a transformed

epithelial

cell

line

(NL-20)

using

(6S,9aS)-6-(4-hydroxybenzyl)-N-benzyl-8-

(naphthalen-1-ylmethyl)-4,7-dioxo-hexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxamide (ICG-001) , a small catenin inhibitor, as a control. Among all the synthetic derivatives, nine compounds (66-74) were found to inhibit Wnt activity with promising IC50 values ranging between 0.067 to 2.03 µM. Compound 68 was the most potent molecule and could be used to treat IPF (Fig. 19).149 In 2014, Gregory et al. filed a patent on compounds with apoptosis signal-regulating kinase (ASK) inhibitory potential and which could be used to treat an ASK-mediated disease such as IPF. ASK phosphorylation can lead to many serious conditions, including IPF. In this aspect, ASK inhibitors define a key role in the treatment of this fatal lung disease. All the synthesized derivatives were evaluated against ASK1 kinase using a TR-FRET ASK1 kinase assay which determines the amount of phosphate transferred from ATP to a peptide substrate. Fluorescence was measured at 665 nm and IC50 values were calculated. All the derivatives inhibited the kinase ASK1 significantly, and 75 was found to be the most potent inhibitor with IC50= 0.7 nM (Fig. 19).150

ACS Paragon Plus Environment

Page 53 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Figure 19. Patented compounds (66-75) for the treatment of IPF

In 2012, Marcello Allegretti et al. published a patent on 2-phenylpropionic acid and its derivatives which are useful for inhibition of chemotactic activation of neutrophils and can be further utilized for prevention and treatment of pathological conditions such as IPF. The compounds were evaluated in vitro as inhibitors of chemotaxis of polymorphonuclear leukocytes (PMN leukocytes) induced by fractions of interleukins (IL-8), GRO-α, and C5a. Compounds 76 and 77 were found to be most potent, inducing significant inhibition of PMN migration (Fig. 20).151 In 2011, Alessio Moriconi et al. patented 2-aryl-acetic acid derivatives for the treatment of IPF

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 54 of 99

by their inhibition of the chemotactic activation of neutrophils. Compounds were tested in vitro for their ability to inhibit chemotaxis of PMN leukocytes induced by IL-8, and GRO-α. Compounds 78 and 79 showed the highest percentage inhibition of IL-8 induced PMN chemotaxis and GRO induced PMN chemotaxis (Fig. 20).152 In 2009, Leslie Holsinger et al. patented compounds with potential to inhibit Cathepsin B, a lysosome cysteine protease, increased levels of which lead to pulmonary fibrosis and hence can be used to cure IPF. The compounds were evaluated for cathepsin inhibition employing a biochemical assay and IC50 values were determined. Compound 80 was found to possess interesting inhibitory potential (Fig. 20).153 In 2009, Kossen et al. published a patent on compounds used to treat fibrotic disorders by inhibition of p38 MAPK. The activation of p38 MAPK kinase leads to the response of various cytokines associated with inflammation. The enhanced activity of this kinase enzyme can cause pulmonary conditions similar to IPF. The synthesized compounds were screened for p38 MAP kinase inhibition in vitro. Most of the compounds exhibited good inhibitory activity with IC50 = 0.05 - 10 µM. Compounds 81 and 82 were the most potent inhibitors (Fig. 20).154 In 2008, Thomas G. Gant et al. published a patent on N-aryl pyridinones as fibrotic inhibitors based on 83 which can be used in the management of IPF. A dystrophic mouse muscle fibrosis assay was carried out for these compounds and all the compounds displayed good activity in fibrotic disorders (Fig. 20).155

ACS Paragon Plus Environment

Page 55 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Figure 20. Patented compounds (76-83) for the treatment of IPF

In 2006, Barry Hart et al published a patent on fused bicyclic pyrimidine compounds useful in

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 56 of 99

the treatment of related disorders like IPF, with enhanced TGF-β activity. The compounds were assessed for their ability to inhibit TGF-β and it was found that 84 and 85 exhibited the highest potency with low IC50 values (Fig. 21).156 In 2006, Levin et al. patented β-sulfonamide hydroxamic acids as inhibitors of TNF-α converting enzyme (TACE) or matrix metalloproteinase (MMPs) which helps in prevention and treatment of IPF. Compounds were assessed for inhibition of the cleavage of the pro-TNF peptide by TACE using TACE FRET assay and the IC50 values were determined. Compounds 86 and 87 were found to be the most potent (Fig. 21).157

Figure 21. Patented compounds (84-87) for the treatment of IPF

In addition to presenting potent scaffolds with antifibrotic potential, the patent literature has

ACS Paragon Plus Environment

Page 57 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

further expanded the library of the enzymes, targets and factors with a key role in fibrosis. This patent literature, coupled with a clear understanding of the pathogenesis of the disease will certainly be beneficial when exploiting the mediators involved. 7. Conclusions and future perspectives IPF, a chronic dysregulated response to micro injuries with fibroblast hyperplasia and exaggerated ECM deposition resulting in abnormal lung remodeling is a progressive and fatal lung disease. It is well evident that fibrosis is a complicated condition and the probability of a single drug or pathway intervention to be curative is very less. In view of the complex etiology of fibrosis and the broad spectrum pharmacological profile of the perfinedone and nintedanib, it can be ascertained that drugs possesing polypharmacology may prove to be advantageous and efficacious antifibrotic agents as compared to the agents acting on a single target. However, this is a huge challenge for the experts working in this field as the design and discovery of agents possessing polypharmacology often relies on serendipity. Pirfenidone and nintedanib are the two approved drugs for IPF with positive and favorable recommendations. Both the drugs exhibit polypharmacology.158 The mechanism of pirfenidone has been extensively studied and it is categorized as a multiple-targets drug against inflammatory, antioxidative stress and antiproliferative processes. It acts on TNF-α, TGF-β, PDGF, and NF-κβ. As an antifibrotic, Pirfinedone displays broad spectrum efficacy to treat pulmonary, liver, renal, and cardiac muscle fibrosis. Similar to pirfinedone, Nintedanib acts on multiple targets and is a potent oral angiokinase inhibitor that targets the pro-angiogenic pathways

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 58 of 99

mediated by VEGFR1-3, fibroblast growth factor receptor (FGFR) 1-3, and PDGFR α and β.115,159 Both pirfenidone and nintedanib can slow down functional decline of the lung and disease progression but cannot cure the disease. This indicates the collaborative efforts required of medicinal chemists and biologists to design and evaluate new chemical architectures with antifibrotic potential for treatment of IPF. Recently, several new compounds have entered into clinical trials and a significant clinical outcome is awaited. It is quite possible that some of these compounds will emerge as future novel therapeutics for IPF. Various biomarkers and pathways involved in this fatal lung disease have been identified. A potential role for protein kinase inhibitors (PKIs) that target prosurvival signaling in the treatment of pulmonary fibrosis has also been established. This has enabled chemists to rationally synthesize and preclinically evaluate new antifibrotic agents for IPF. Apart from targeting the mediators of inflammation and various kinases, blocking of LPA1 signaling also appears to be a logical therapeutic strategy for IPF. The role of HDACs in the progression of tissue fibrosis has also been reported. Recently, SAHA, an HDAC inhibitor, has been reported in a preclinical study to promote fibroblast apoptosis and ameliorate pulmonary fibrosis.32 This is an exciting advance in the medicinal attributes of HDAC inhibitors and if this preclinical promise of SAHA to attenuate pulmonary fibrosis can be replicated clinically, a variety of similar inhibitors will be available for initial screening as anti-IPF agents. LBH589/panobinostat (pan-HDAC inhibitor), a proven antitumour agent, significantly downregulates collagen biosynthesis and antiapoptotic genes in IPF fibroblast populations and thus pan-HDAC inhibition also presents a therapeutic strategy for

ACS Paragon Plus Environment

Page 59 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

patients with IPF.160 With such positive results, it is really astonishing that an extensive screening program to evaluate such inhibitors for the treatment of IPF by various laboratories working extensively on the development of HDAC inhibitors has not been initiated yet. Numerous inhibitors have been synthesised employing SAHA and LBH589 as the leads and the library of such agents must be evaluated for their potential as antifibrotic agents for IPF. Ultimately, such a program may lead to the discovery of novel HDAC inhibitor as a useful therapeutic agent for IPF or at a minimum, another target for the fatal lung disease will be fully identified. The role of Brd on the profibrotic responses of lung fibroblasts patients with rapidly progressing IPF and mouse bleomycin model of lung fibrosis has been identified in a recent study. It was observed that Brd4 inhibition remarkably attenuates the enhanced migration, proliferation, and IL-6 release observed in lung fibroblasts in patients with IPF. Enhanced histone H4 lysine5 acetylation and association of Brd4 with genes involved in the profibrotic responses in IPF was also observed. Compound 4, a Brd 4 inhibitors at a dose of 200 mg/kg administered orally significantly attenuated the bleomycin induced lung fibrosis in C57BL/6 mice. Overall the study concluded that 4 possesses the potential to inhibit the profibrotic effects of IPF and indicates the promise of Brd4 inhibitors as a novel and efficacious therapy for rapidly progressing IPF. Keeping this in view, the chemist must emphasize on these interesting findings and should work on the design of novel Brd4 inhibitors for this fatal lung disease. Moreover, the existing Brd4 inhibitors shall also be evaluated for their antifibrotic effects in IPF.30

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 60 of 99

In view of the favorable outcomes with polypharmacological interventions, it can be anticipated that dual inhibitors of Brd4-HDAC, HDAC-LPA1, Brd4-4-LPA1 along with agents targeting various kinases may be a logical drug design strategy in future. These multitargeting agents can be synthesised via molecular hybridization technique which comprises the incorporation of two drug pharmacophores in a single chemical architecture. Moreover such hybrid drugs can also counterbalance the known side effects associated with the other hybrid part.161 It is really a high time for the experts to rationally design such scaffolds for the treatment of IPF. The link between thrombotic vascular events and IPF is supported by compelling evidences. Despite of the conflicting outcomes of the clinical trials of anticoagulation in IPF, it can still be concluded that the manipulation of the coagulation system plays a role in IPF pathogenesis and future investigations should be directed towards the exploration of the mechanisms underlying the prothrombotic state in IPF. The effects of new classes of anticoagulants in IPF also need to be assesed.37 This compilation presents the pathogenesis, therapeutic interventions and the treatment approaches for IPF. Based on the new concept of pathogenesis of IPF, several targets are in the development pipeline. Activator protein 1 (AP-1) related to regulation of cytokines and chemokines and NADPH oxidase isoform 4 (Nox4) inhibitors capable of attenuating pulmonary fibrosis represent such targets. 162 The new drugs or therapeutic inventions and the novel pathways for IPF await full discovery, understanding and establishment. IPF is now viewed more as a neoproliferative disorder

ACS Paragon Plus Environment

Page 61 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

of the lungs. Categorizing IPF as a cancer-like disease provides a better and clearer understanding of the pathogenesis of the disease. The pathogenic pathways common to both cancer and IPF offer much scope for new clinical trials with existing anticancer agents and drug combinations. The present review article also encompasses the design strategies employed for the synthesis of agents with promising activity for the treatment of IPF. Over the last few years, the researchers have identified some promising scaffolds, at the preclinical level, which display remarkable antifibrotic potential in pulmonary fibrosis. In addition to design strategies, the article also highlights the structure activity relationships and the mechanistic insights revealed during the biological evaluation of these agents. The research literature indicates that chemists have extensively attempted to evaluate pirfenidone derivatives and their efforts have been aimed mainly at overcoming the drawbacks of pirfenidone such as its short half life, low efficacy and requirement of high doses. The expertise of formulation chemists to improve the pharmacokinetic properties of pirfenidone can lead to new dimensions in pharmacological profile of the compound. However, the need of the hour is the search of novel agents with antifibrotic potential in IPF. The medicinal chemist should draw its attention towards the design of such novel scaffold relying on the biologist and the formulation experts to evaluate already existing agents and modify the pharmacokinetic parameters. Thirteen patents have been published during the last ten years detailing the synthesis and evaluation of antifibrotic agents for IPF. This review article emphasizes the patent literature with an overview of the chemical structures and the IC50/GI50 values indicating the inhibitory effects. The

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

patent

literature

presents

activity

profiles

of

Page 62 of 99

coumarins,

isoquinolinones,

pyrrolopyrimidinecarboxamides, pyrazolo-pyridines, 2-aryl acetic or propanoic acid derivatives and sulfonamide hydroxamic acids for the treatment of IPF. The biological evaluation of most of the patented compounds has been limited to in vitro studies, and in vivo pharmacological evaluation with detailed mechanistic studies is necessary. Some of the patented molecules have displayed promising inhibitory effects with IC50 values in the low micromolar range and even at the nanomolar level. With a dozen of antifibrotic agents possessing exciting preclinical potential in the armory, it can be anticipated that some of them will advance to clinical investigation. At present, the difficult diagnosis and high mortality rate in IPF pose the main challenges for the researchers working in this field. A reliable and fast diagnosis technique and effective treatment are highly desirable. A timely diagnosis of IPF requires high resolution computed tomography (HRCT) and/or surgical lung biopsy. Currently, there are no other simple, quick and effective means of diagnosis for physicians and the identification of diagnostic biomarkers will be of great help for the physician especially when the HRCT or biopsy cannot be obtained. Biomarkers can provide valuable information such as pathogenesis, prognosis and therapeutic outcomes. Several molecular biomarkers for IPF such as surfactant proteins A and D (SPA and SPD), MMP1 and MMP7 and periostin have already been outlined.162 All these biomarkers are highly expressed in the patients with IPF and a detailed investigation could lead to their emergence as effective clinical tools for accurate diagnosis of IPF.

ACS Paragon Plus Environment

Page 63 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Last but not the least, non pharmacological approaches also holds enough promise and have been recognized as effective measures for IPF. Among these approaches, lung transplantation (LTx) is an accepted therapy for patients with chronic, end-stage lung disease for whom no effective medical therapy exists. LTx confers quality of life and survival benefits and is reported to be the best available therapy for selected IPF patients. Based on the recommendations in the guidelines, IPF patients should be referred for transplantation in the presence of a DLCO below 39%, a greater than 10% FVC decline over 6 months or desaturation under 88% in pulse oximetry during a 6-minute walking test.163-168 Pulmonary rehabilitation (PR) has also proved its effectiveness in alleviating symptoms and improving exercise tolerance, functional capacity, dyspnea scores, leg strength and quality of life in patients with IPF. However, the limitation and the long-term effects of PR should be observed in a detailed manner and further investigations are required.169-175 In addition, beneficial effects can also be observed for patients with IPF if the comorbidities such as GERD, pulmonary hypertension and obstructive sleep apnea which are frequently associated with IPF can be taken care of.176-181

ACKNOWLEDGMENTS This research were supported by the Ministry of Science and Technology of the Republic of China (grant no. MOST 103-2113-M-038-001-MY3).

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 64 of 99

ABBREVIATIONS USED AECs, Alveolar epithelial cells; AP-1, Activator protein-1; ASK, Apoptosis signal-regulating kinases; ATX, Autotaxin; BALF, Bonchoalveolar lavage fluid; BLTx, Bilateral lung transplantation; CPAP, Continuous positive airway pressure; CTGF, Connective tissue growth factor; CYP450; Cytochrome p450; DLCO, Carbon monoxide diffusing capacity; ECM, Extracellular matrix; FGF, Fibroblast growth factor; FVC, Forced vital capacity; GERD, Gastroesophageal reflux disease; HDAC, Histone deacetylase; HP, Hydroxyproline; HRCT, High resolution computed tomography; HTS, High throughput screening; IIP, Idiopathic interstitial pneumonia; IL-13, Interleukin-13; ILD, Interstitial lung disease; IPF, Idiopathic pulmonary fibrosis; JNK, c-Jun N-terminal kinase; LDH, Lactate dehydrogenase; LPA, Lysophosphatidic acid; LPA1, Lysophosphatidic acid receptor 1; LPC, Lysophosphatidyl choline; LPS, Lipopolysaccharide; LTx, Lung transplantation; MMP, matrix metalloproteinase; mTOR, mammalian homolog of target of rapamycin; NAC, N-acetylcysteine; NHLF, Normal human lung fibroblasts; Nox 4, NADPH oxidase isoform 4; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; OSA, Obstructive sleep apnea; PAI-1, Plasminogen activator inhibitor-1; PAR1, Proteinase activated receptors; PDE, Phosphodiesterase; PDGF, Platelet-derived growth factor; PKIs, Protein kinase inhibitors; PMN leukocytes, Polymorphonuclear leukocytes; PPIs, Proton pump inhibitors; PR, Pulmonary rehabilitation; ROS, Reactive oxygen species; SLTx, Single lung transplantation; SPA and SPD, Surfactant proteins A and D; TACE, TNF-α converting enzyme; TERC, Telomerase RNA component; TERT, Telomerase reverse transcriptase; TGF-β, Transforming

ACS Paragon Plus Environment

Page 65 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

growth factor β; TH2 cell, T helper 2 cell; TNF, Tumor necrosis factor; VEGF, Vascular endothelial growth factor; UIP, Usual interstitial pneumonia.

CORRESPONDING AUTHOR INFORMATION *E-mail: [email protected]. Phone: +886-2-2736-1661, extension 6130.

BIOGRAPHIES Yi-Min Liu received her Ph.D degree in Pharmacy from College of Pharmacy, Taipei Medical University, Taipei, Taiwan, under the supervision of Professor Jing-Ping Liou. Her research work is focused at the rational drug design of small molecule inhibitors of relevant drug targets and optimization of synthetic procedures for the preparation of compounds along with structure activity relationship studies. She is currently a Post Doctoral Fellow in the Department of Medicinal Chemistry at the same institution. Kunal Nepali obtained his Ph.D degree in Pharmaceutical Chemistry in the year 2012 from ISF College of Pharmacy, Moga, Punjab, India. He is currently a Post Doctoral Fellow in the Department of Medicinal Chemistry, Taipei Medical University, Taiwan working under the directions and supervision of Prof. Jing Ping Liou. His research area is focused at the design and synthesis of new chemical architectures with bioactive potential. Prior to his appointment a Post Doctoral Fellow, he was an Assistant Professor in Department of Pharmaceutical Sciences, Guru Nanak Dev University,

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 66 of 99

Punjab, India. Jing-Ping Liou is a Professor of Medicinal Chemistry and Associate Dean in the College of Pharmacy, Taipei Medical University, Taiwan. He received his Ph.D degree in the year 2000 from the College of Medicine, National Taiwan University, Taiwan. His scientific interests are centered at the design and synthesis of novel molecular entities as future therapeutics to address the pharmacological problems that lie at the interface of chemistry and biology. He also collaborates with the industrial sector for the optimization of synthetic protocols for rationally designed inhibitors with the potential of modulating the functions of biological targets.

REFERENCES (1) Raghu, G.; Collard, H. R.; Egan, J. J.; Martinez, F. J.; Behr, J.; Brown, K. K.; Colby, T. V.; Cordier, J.-F.; Flaherty, K. R.; Lasky, J. A.; Lynch, D. A.; Ryu, J. H.; Swigris, J. J.; Wells, A. U.; Ancochea, J.; Bouros, D.; Carvalho, C.; Costabel, U.; Ebina, M.; Hansell, D. M.; Johkoh, T.; Kim, D. S.; King, T. E. Jr.; Kondoh, Y.; Myers, J.; Müller, N. L.; Nicholson, A. G.; Richeldi, L.; Selman, M.; Dudden, R. F.; Griss, B. S.; Protzko, S. L.; Schünemann, H. J. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care. Med. 2011, 183, 788-824. (2) (a) Spagnolo, P.; Sverzellati, N.; Rossi, G.; Cavazza, A.; Tzouvelekis, A.; Crestani, B.; Vancheri, C. Idiopathic pulmonary fibrosis: an update. Ann. Med. 2015, 47, 15-27; (b) Selman, M.; Thannickal,

ACS Paragon Plus Environment

Page 67 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

V. J.; Pardo, A.; Zisman, D. A.; Martinez, F. J.; Lynch, J. P. 3rd. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 2004, 64, 405-430; (c) Ziobro, R.; Henry, B.; Edwards, M. J.; Lentsch, A. B.; Gulbins, E. Ceramide mediates lung fibrosis in cystic fibrosis. Biochem. Biophys. Res. Commun. 2013, 434, 705-709; (d) Wilson, M. S.; Wynn, T. A. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009, 2, 103-121; (e) Ma, Z.; Pan, Y.; Huang, W.; Yang, Y.; Wang, Z.; Li, Q.; Zhao, Y.; Zhang, X.; Shen, Z. Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents. Bioorg. Med. Chem. Lett. 2014, 24, 220-223. (3) Kim, H. J.; Perlman, D.; Tomic, R. Natural history of idiopathic pulmonary fibrosis. Respir. Med. 2015, 109, 661-670. (4) Chakraborty, S.; Chopra, P.; Ambi, S. V.; Dastidar S. G.; Ray, A. Emerging therapeutic interventions for idiopathic pulmonary fibrosis. Expert. Opin. Investig. Drugs. 2014, 23, 893-910. (5) Raghu, G.; Weycker, D.; Edelsberg, J.; Bradford, W. Z.; Oster, G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 2006, 174, 810-816. (6) Nalysnyk, L.; Cid-Ruzafa, J.; Rotella, P.; Esser, D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur. Respir. Rev. 2012, 21, 355-361. (7) Olson, A. L.; Swigris, J. J.; Lezotte, D. C.; Norris, J. M.; Wilson, C. G.; Brown, K. K. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am. J. Respir. Crit. Care. Med. 2007, 176, 277-284.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 68 of 99

(8) Hutchinson, J.; Fogarty, A.; Hubbard, R.; McKeever, T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur. Respir. J. 2015, 46, 604-606. (9) Gribbin, J.; Hubbard, R. B.; Le Jeune, I.; Smith, C. J. P.; West, J.; Tata, L. J. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax 2006, 61, 980-985. (10) Navaratnam, V.; Fleming, K. M.; West, J.; Smith, C. J.; Jenkins, R. G.; Fogarty, A.; Hubbard, R. B. The rising incidence of idiopathic pulmonary fibrosis in the UK. Thorax 2011, 66, 462-467. (11) Macneal, K.; Schwartz, D. A. The genetic and environmental causes of pulmonary fibrosis. Proc. Am. Thorac. Soc. 2012, 9, 120-125. (12) Yang, I. V.; Schwartz, D. A. Epigenetics of idiopathic pulmonary fibrosis. Transl. Res. 2015, 165, 48-60. (13) Wolters, P. J.; Collard, H. R.; Jones, K. D. Pathogenesis of idiopathic pulmonary fibrosis. Annu. Rev. Pathol. 2014, 9, 157-179. (14) National Institutes of Health. https://www.nhlbi.nih.gov/ (accessed May 20, 2016). (15) Rafii, R.; Juarez, M. M.; Albertson, T. E.; Chan, A. L. A review of current and novel therapies for idiopathic pulmonary fibrosis. J. Thorac. Dis. 2013, 5, 48-73. (16) Raghu, G.; Rochwerg, B.; Zhang, Y.; Cuello Garcia, C. A.; Azuma, A.; Behr, J.; Brozek, J. L.; Collard, H. R.; Cunningham, W.; Homma, S.; Johkoh, T.; Martinez, F. J.; Myers, J.; Protzko, S. L.; Richeldi, L.; Rind, D.; Selman, M.; Theodore, A.; Wells, A. U.; Hoogsteden, H.; Schünemann, H. J. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary

ACS Paragon Plus Environment

Page 69 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

fibrosis. Am. J. Respir. Crit. Care. Med. 2015, 192, e3-e19. (17) Selman, M.; King Jr, T. E.; Pardo, A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann. Intern. Med. 2001, 134, 136151. (18) King Jr, T. E.; Pardo, A.; Selman, M. Idiopathic pulmonary fibrosis. Lancet 2011, 378, 19491961. (19) Ahluwalia, N.; Shea, B. S.; Tager, A. M. New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses. Am. J. Respir. Crit. Care. Med. 2014, 190, 867-878. (20) Chambers, R. C.; Mercer, P. F. Mechanisms of alveolar epithelial injury, repair, and fibrosis. Ann. Am. Thorac. Soc. 2015, 12, S16-S20. (21) Fulton, B. G.; Ryerson, C. J. Managing comorbidities in idiopathic pulmonary fibrosis. Int. J. Gen. Med. 2015, 8, 309-318. (22) Kreuter, M.; Ehlers-Tenenbaum, S.; Palmowski, K.; Bruhwyler, J.; Oltmanns, U.; Muley, T.; Heussel, C. P.; Warth, A.; Kolb, M.; Herth, F. J. F. Impact of comorbidities on mortality in patients with idiopathic pulmonary fibrosis. PLoSONE 2016, 11, e0151425. (23) Lee, C. M.; Lee, D. H.; Ahn, B. K.; Hwang, J. J.; Yoon, H.; Shin, C. M.; Park, Y. S.; Kim, N. Protective effect of proton pump inhibitor for survival in patients with gastroesophageal reflux disease and idiopathic pulmonary fibrosis. J. Neurogastroenterol. Motil. 2016, 22, 444-451.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 70 of 99

(24) Luppi, F.; Spagnolo, P.; Cerri, S.; Richeldi, L. The big clinical trials in idiopathic pulmonary fibrosis. Curr. Opin. Pulm. Med. 2012, 18, 428-432. (25) Demedts, M.; Behr, J.; Buhl, R.; Costabel, U.; Dekhuijzen, R.; Jansen, H. K.; MacNee, W.; Thomeer, M.; Wallaert, B.; Laurent, F.; Nicholson, A. G.; Verbeken, E. K.; Verschakelen, J.; Flower, C. D. R.; Capron, F.; Petruzzelli, S.; De Vuyst, P.; van den Bosch, J. M. M.; Rodriguez-Becerra, E.; Corvasce, G.; Lankhorst, I.; Sardina, M.; Montanari, M.; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2005, 353, 2229-2242. (26) Idiopathic Pulmonary Fibrosis Clinical Research Network; Raghu, G.; Anstrom, K. J.; King, T. E. Jr.; Lasky, J. A.; Martinez, F. J. A.; Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012, 366, 1968-1977. (27) Idiopathic Pulmonary Fibrosis Clinical Research Network; Martinez, F. J.; de Andrade, J. A.; Anstrom, K. J.; King, T. E. Jr.; Raghu, G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2093-2101. (28) Behr, J.; Bendstrup, E.; Crestani, B.; Günther, A.; Olschewski, H.; Sköld, C. M.; Wells, A.; Wuyts, W.; Koschel, D.; Kreuter, M.; Wallaert, B.; Lin, C. Y.; Beck, J.; Albera, C. Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, Phase 2 trial. Lancet. Respir. Med. 2016, 4, 445-453. (29) Comer, B. S.; Ba, M.; Singer, C. A.; Gerthoffer, W. T. Epigenetic targets for novel therapies of lung diseases. Pharmacol. Ther. 2015, 147, 91-110.

ACS Paragon Plus Environment

Page 71 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(30) Tang, X.; Peng, R.; Phillips, J. E.; Deguzman, J.; Ren, Y.; Apparsundaram, S.; Luo, Q.; Bauer, C. M.; Fuentes, M. E.; DeMartino, J. A., Tyagi, G.; Garrido, R.; Hogaboam, C .M.; Denton, C. P.; Holmes, A. M.; Kitson, C.; Stevenson, C. S.; Budd, D. C. Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis. Am J. Pathol. 2013, 183, 470-479. (31) Tang, X.; Peng, R.; Ren, Y.; Apparsundaram, S.; Deguzman, J.; Bauer, C. M.; Hoffman, A. F.; Hamilton, S.; Liang, Z.; Zeng, H.; Fuentes, M. E.; DeMartino, J. A., Kitson, C.; Stevenson, C. S.; Budd, D. C. BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in belomycin-induced pulmonary fibrosis. Mol. Pharmacol. 2013, 83, 283-293. (32) Sanders, Y. Y.; Hagood, J. S.; Liu, H.; Zhang, W.; Ambalavanan, N.; Thannickal, V. J. Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. Eur. Respir. J. 2014, 43, 1448-1458. (33) Cronkhite, J. T.; Xing, C.; Raghu, G.; Chin, K. M.; Torres, F.; Rosenblatt, R. L.; Garcia, C. K. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 2008, 178, 729-737. (34) Seibold, M. A.; Wise, A. L.; Speer, M. C.; Steele, M. P.; Brown, K. K.; Loyd, J. E.; Fingerlin, T. E.; Zhang, W.; Gudmundsson, G.; Groshong, S. D.; Evans, C. M.; Garantziotis, S.; Adler, K. B.; Dickey, B. F.; du Bois, R. M.; Yang, I. V.; Herron, A.; Kervitsky, D.; Talbert, J. L.; Markin, C.; Park,

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 72 of 99

J.; Crews, A. L.; Slifer, S. H.; Auerbach, S.; Roy, M. G.; Lin, J.; Hennessy, C. E.; Schwarz, M. I.; Schwartz, D. A. A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 2011, 364, 1503-1512. (35) Hunninghake, G. M.; Hatabu, H.; Okajima, Y.; Gao, W.; Dupuis, J.; Latourelle, J. C.; Nishino, M.; Araki, T.; Zazueta, O. E.; Kurugol, S.; Ross, J. C.; San José Estépar, R.; Murphy, E.; Steele, M. P.; Loyd, J. E.; Schwarz, M. I.; Fingerlin, T. E.; Rosas, I. O.; Washko, G. R.; O'Connor, G. T.; Schwartz, D. A. MUC5B promoter polymorphism and interstitial lung abnormalities. N. Engl. J. Med. 2013, 368, 2192-2200. (36) Guo, S.; DiPietro, L. A. Factors affecting would healing. J. Dent. Res. 2010, 89, 219-229. (37) Crooks, M. G.; Hart, S. P. Coagulation and anticoagulation in idiopathic pulmonary fibrosis. Eur. Respir. Rev. 2015, 24, 392-399. (38) Navaratnam, V.; Fogarty, A. W.; McKeever, T.; Thompson, N.; Jenkins, G.; Johnson, S. R.; Dolan, G.; Kumaran, M.; Pointon, K.; Hubbard, R. B. Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study. Thorax 2014, 69, 207-215. (39) Noth, I.; Anstrom, K. J.; Calvert, S. B.; de Andrade, J.; Flaherty, K. R.; Glazer, C.; Kaner, R. J.; Olman, M. A.; Idiopathic pulmonary fibrosis clinical network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 2012, 186, 88-95. (40) Kreuter, M.; Wijsenbeek, M. S.; Vasakova, M.; Spagnolo, P.; Kolb, M.; Costabel, U.; Weycker,

ACS Paragon Plus Environment

Page 73 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

D.; Kirchgaessler, K.-U.; Maher, T. M. Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis. Eur. Respir. J. 2016, 47, 1776-1784. (41) Bogatkevich, G. S.; Ludwicka-bradley, A.; Silver, R. M. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis. Rheum. 2009, 60, 3455-3464. (42) Bogatkevich, G. S.; Ludwicka-bradley, A.; Nietert, P. J.; Akter, T.; van Ryn, J.; Silver, R. M. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis. Rheum. 2011, 63, 1416-1425. (43) Scotton, C. J.; Krupiczojc, M. A.; Königshoff, M.; Mercer, P. F.; Lee, Y. C.; Kaminski, N.; Morser, J.; Post, J. M.; Macher, T. M.; Nicholson, A. G.; Moffatt, J. D.; Laurent, G. J.; Derian, C. K.; Eickelberg, O.; Chambers, R. C. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest. 2009, 119, 2550-2563. (44) Lipson, K. E.; Wong, C.; Teng, Y.; Spong, S. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis. Tissue. Repair. 2012, 5, S24. (45) Kono, M.; Nakamura, Y.; Suda, T.; Kato, M.; Kaida, Y.; Hashimoto, D.; Inui, N.; Hamada, E.; Miyazaki, O.; Kurashita, S.; Fukamachi, I.; Endo, K.; Ng, P.-S.; Takehara, K.; Nakamura, H.; Maekawa, M.; Chida, K. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin. Chim. Acta. 2011, 412, 2211-2215. (46) Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 2015,

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 74 of 99

15,271-282. (47) Murray, L. A.; Zhang, H.; Oak, S. R.; Coelho, A. L.; Herath, A.; Flaherty, K. R.; Lee, J.; Bell. M.; Knight, D. A.; Martinez, F. J.; Sleeman, M. A.; Herzog, E. L.; Hogaboam, C. M. Targeting interleukin-13 with tralokinumab attenuates lung fibrosis and epithelial damage in a humanized SCID idiopathic pulmonary fibrosis model. Am. J. Respir. Cell. Mol. Biol. 2014, 50, 985-994. (48) ClinicalTrials.gov. A study of lebrikizumab in patients with idiopathic pulmonary fibrosis. https://clinicaltrials.gov/ct2/show/NCT01872689 (access May 20, 2016). (49) Wilson, M. S.; Wynn, T. A. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal. Immunol. 2009, 2, 103-121. (50) Staitieh, B. S.; Renzoni, E. A.; Veeraraghavan, S. Pharmacologic therapies for idiopathic pulmonary fibrosis, past and future. Ann Med. 2015, 47, 100-105. (51) Horan, G. S.; Wood, S.; Ona, V.; Li, D. J.; Lukashev, M. E.; Weinreb, P. H.; Simon, K. J.; Hahm, K.; Allaire, N. E.; Rinaldi, N. J.; Goyal, J.; Feghali-Bostwick, C. A.; Matteson, E. L.; O'Hara, C.; Lafyatis, R.; Davis, G. S.; Huang, X.; Sheppard, D.; Violette, S. M. Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care. Med. 2008, 177, 56-65. (52) Porte, J.; Jenkins, G. Assessment of the effect of potential antifibrotic compounds on total and αvβ6 integrin-mediated TGF-β activation. Pharma. Res. Per. 2014, 2, e00030. (53) ClinicalTrials.gov. STX-100 in patients with idiopathic pulmonary fibrosis (IPF).

ACS Paragon Plus Environment

Page 75 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

http://clinicaltrials.gov/ct2/show/NCT01371305 (access May 20, 2016). (54) Raghu, G.; Scholand, M. B.; de Andrade, J.; Lancaster, L.; Mageto, Y.; Goldin J.; Brown, K. K.; Flaherty, K. R.; Wencel, M.; Wanger, J.; Neff, T.; Valone, F.; Stauffer, J.; Porter, S. FG-3019 anticonnective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis. Eur. Respir. J. 2016, 47, 1321-1323. (55) José, R. J.; Williams, A. E.; Chambers, R. C. Proteinase-activated receptors in fibroproliferative lung disease. Thorax 2014, 69, 190-192. (56) Howell, D. C. J.; Johns, R. H.; Lasky, J. A.; Shan, B.; Scotton, C. J.; Laurent, G. J.; Chambers, R. C. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am. J. Pathol. 2005, 166, 1353-1365. (57) Liu, R.-M. Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis. Antioxid. Redox. Signal. 2008, 10, 303-319. (58) Osterholzer, J. J.; Christensen, P. J.; Lama, V.; Horowitz, J. C.; Hattori, N.; Subbotina, N.; Cunningham, A.; Lin, Y,; Murdock, B. J.; Morey, R. E.; Olszewski, M. A.; Lawrence, D. A.; Simon, R. H. Sisson, T. H. PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury. J. Pathol. 2012, 228, 170-180. (59) Omori, K.; Hattori, N.; Senoo, T.; Takayama, Y.; Masuda, T.; Nakashima, T.; Iwamoto, H.; Fujitaka, K.; Hamada, H.; Kohno, N. Inhibition of plasminogen activator inhibitor-1 attenuates transforming growth factor-β-dependent epithelial mesenchymal transition and differentiation of

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 76 of 99

fibroblasts to myofibroblasts. PLoSONE 2016, 11, e0148969. (60) Tager, A. M.; LaCamera, P.; Shea, B. S.; Campanella, G. S.; Selman, M.; Zhao, Z.; Polosukhin, V.; Wain, J.; Karimi-Shah, B. A.; Kim, N. D.; Hart, W. K.; Pardo, A.; Blackwell, T. S.; Xu, Y.; Chun, J.; Luster, A. D. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 2008, 14, 45-54. (61) Funke, M.; Zhao, Z.; Xu, Y.; Chun, J.; Tager, A. M. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am. J. Respir. Cell. Mol. Biol. 2012, 46, 355-364. (62) Swaney, J. S.; Chapman, C.; Correa, L. D.; Stebbins, K. J.; Bundey, R. A.; Prodanovich, P. C.; Fagan, P.; Baccei, C. S.; Santini, A. M.; Hutchinson, J. H.; Seiders, T. J.; Parr, T. A.; Prasit, P.; Evans, J. F.; Lorrain, D. S. A novel, orally active LPA1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br. J. Pharmacol. 2010, 160, 1699-1713. (63) González-Gil, I.; Zian, D.; Vázquez-Villa, H.; Ortega-Gutiérrez, S.; López-Rodríguez, M. L. The status of the lysophosphatidic acid receptor type 1 (LPA1R). Med. Chem. Commun. 2015, 6, 1323. (64) ClinicalTrials.gov. Safety and efficacy of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. https://clinicaltrials.gov/ct2/show/NCT01766817 (access May 20, 2016). (65)

U.S.

Food

and

Drug

Administration.

Novel

drug

approvals

http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm429247.htm

ACS Paragon Plus Environment

for

2014. (access

Page 77 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

May 20, 2016). (66)

Data

were

generated

using

Micromedex® .

http://www.micromedexsolutions.com/micromedex2/librarian (access May 20, 2016). (67) Kim, E. S.; Keating, G. M. Pirfenidone: a review of its use in idiopathic pulmonary fibrosis. Drugs 2015, 75, 219-230. (68) Xaubet, A.; Serrano-Mollar, A.; Ancochea, J. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert. Opin. Pharmacother. 2014, 15, 275-281. (69) Poletti, V.; Ravaglia, C.; Tomassetti, S. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert. Rev. Respir. Med. 2014, 8, 539-545. (70) Hisatomi, K.; Mukae, H.; Sakamota, N.; Ishimatsu, Y.; Kakugawa, T.; Hara, S.; Fujita, H.; Nakamichi, S.; Oku, H.; Urata, Y.; Kubota, H.; Nagata, K.; Kohno, S. Pirfenidone inhibits TGF-β1induced over-expression of collagen type I and heat shock protein 47 in A549 cells. BMC. Pulm. Med. 2012, 12, 24. (71) Akhurst, R. J.; Hata, A.; Targeting the TGFβ signaling pathway in disease. Nat. Rev. Drug. Discov. 2012, 11, 790-811. (72) Nakazato, H.; Oku, H.; Yamane, S.; Tsuruta, Y.; Suzuki, R. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-α at the translational level. Eur. J. Pharmacol. 2002, 446, 177-185. (73) Oku, H.; Nakazato, H.; Horikawa, T.; Tsuruta, Y.; Suzuki, R. Pirfenidone suppresses tumor

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 78 of 99

necrosis factor-α, enhances interleukin-10 and protects mice from endotoxic shock. Eur. J. Pharmacol. 2002, 446, 167-176. (74) Misra, H. P.; Rabideau, C. Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals. Mol. Cell. Biochem. 2000, 204, 119-126. (75) Taniguchi, H.; Ebina, M.; Kondoh, Y.; Ogura, T.; Azuma, A.; Suga, M.; Taguchi, Y.; Takahashi, H.; Nakata, K.; Sato, A.; Takeuchi, M.; Raghu, G.; Kusoh, S.; Nukiwa, T.; the Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur. Respir. J. 2010, 35, 821829. (76) Noble, P. W.; Albera, C.; Bradford, W. Z.; Costabel, U.; Glassberg, M. K.; Kardatzke, D.; King, T. E. Jr.; Lancaster, L.; Sahn, S. A.; Szwarcberg, J.; Valeyre, D.; du Bois, R. M.; CAPACITY Study group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomized trials. Lancet 2011, 377, 1760-1769. (77) King, T. E. Jr.; Bradford, W. Z.; Castro-Bernardini, S.; Fagan, E. A.; Glaspole, I.; Glassberg, M. K.; Gorina, E.; Hopkins, P. M.; Kardatzke, D.; Lancaster, L.; Lederer, D. J.; Nathan, S. D.; Pereira, C. A.; Sahn, S. A.; Sussman, R.; Swigris, J. J.; Noble, P. W.; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2083-2092. (78) Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.; Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt, U.; Walter, R.; Hilberg, F. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted

ACS Paragon Plus Environment

Page 79 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

indolinone (BIBF1120). J. Med. Chem. 2009, 52, 4466-4480. (79) Dimitroulis, I. A. Nintedanib: a novel therapeutic approach for idiopathic pulmonary fibrosis. Respir. Care. 2014, 59, 1450-1455. (80) Roth, G. J.; Binder, R.; Colbatzky, F.; Dallinger, C.; Schlenker-Herceg, R.; Hilberg, F.; Wollin, S.-L.; Kaiser, R. Nintedanib: from discovery to the clinic. J. Med. Chem. 2015, 58, 1053-1063. (81)

Data

were

generated

using

Micromedex® .

http://www.micromedexsolutions.com/micromedex2/librarian (access May 20, 2016). (82) Noskovičová, N.; Petřek, M.; Eickelberg, O.; Heinzelmann, K. Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am. J. Respir. Cell. Mol. Biol. 2015, 52, 263-284. (83) Andrea, J.; Gallini, R.; Betsholtz, C. Role of platelet-derived growth factors in physiology and medicine. Genes. Dev. 2008, 22, 1276-1312. (84) Nishioka, Y.; Azuma, M.; Kishi, M.; Aono, Y. Targeting platelet-derived growth factors as a therapeutic approach in pulmonary fibrosis. J. Med. Invest. 2013, 60, 175-183. (85) Abdollahi, A.; Li, M.; Ping, G.; Plathow, C.; Domhan, S.; Kiessling, F.; Lee. L. B.; McMahon, G.; Gröne, H.-J.; Lipson, K. E.; Huber, P. E. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J. Exp. Med. 2005, 201, 925-935. (86) Bonner, J. C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine. Growth. Factor. Rev. 2004, 15, 255-273.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 80 of 99

(87) Dosanjh, A. The fibroblast growth factor pathway and its role in the pathogenesis of lung disease. J. Interferon. Cytokine. Res. 2012, 32, 111-114. (88) Yan, Z.; Kui, Z.; Ping, Z. Reviews and prospectives of signaling pathway analysis in idiopathic pulmonary fibrosis. Autoimmun. Rev. 2014, 13, 1020-1025. (89) Ou, X.-M.; Li, W.-C.; Liu, D.-S.; Li, Y.-P.; Wen, F.-Q.; Feng, Y.-L.; Zhang, S.-F.; Huang, X.-Y.; Wang, T.; Wang, K.; Wang, X.; Chen, L. VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice. Int. Immunopharmacol. 2009, 9, 70-79. (90) Chaudhary, N. I.; Roth, G. J.; Hilberg, F.; Müller-Quernheim, J.; Prasse, A.; Zissel, G.; Schnapp, A.; Park, J. E. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur. Respir. J. 2007, 29, 976-985. (91) Hostettler, K. E.; Zhong, J.; Papakonstantinou, E.; Karakiulakis, G.; Tamm, M.; Seidel, P.; Sun, Q.; Mandal, J.; Lardinois, D.; Lambers, C.; Roth. M. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir. Res. 2014, 15, 157. (92) Inomata, M.; Nishioka, Y.; Azuma, A. Ninedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis. Core. Evid. 2015, 10, 89-98. (93) Bonella, F.; Stowasser, S.; Wollin, L. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib. Drug. Des. Devel. Ther. 2015, 9, 6407-6419. (94) Richeldi, L.; Costabel, U.; Selman, M.; Kim, D. S.; Hansell, D. M.; Nicholson, A. G.; Brown, K. K.; Flaherty, K. R.; Noble, P. W.; Raghu, G.; Brun, M.; Gupta, A.; Juhel, N.; Klüglich, M.; du Bois, R.

ACS Paragon Plus Environment

Page 81 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

M. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2011, 365, 1079-1087. (95) Richeldi, L.; du Bois, R. M.; Raghu, G.; Azuma, A.; Brown, K. K.; Costabel, U.; Cottin, V.; Flaherty, K. R.; Hansell, D. M.; Inoue, Y.; Kim, D. S.; Kolb, M.; Nicholson, A. G.; Noble, P. W.; Selman, M.; Taniguchi, H.; Brun, M.; Le Maulf, F.; Girard, M.; Stowasser, S.; Schlenker-Herceg, R.; Disse, B.; Collard, H. R.; INPULSIS trial investigators. N. Engl. J. Med. 2014, 370, 2071-2082. (96) Crestani, B.; Ogura, T.; Pelling, K.; Coeck, C.; Quaresma, M.; Kreuter, M.; Kaye, M. Interim analysis of nintedanib in an open-label extension of the INPULSIS® trials (INPULSIS® -ON). Eur. Respir. J. 2015, 46, OA4495. (97) Hecker, L.; Vittal, R.; Jones, T.; Jagirdar, R.; Luckhardt, T. R.; Horowitz, J. C.; Pennathur, S.; Martinez, F. J.; Thannickal, V. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. J. Nat. Med. 2009, 15, 1077-1081. (98) (a) Laleu, B.; Gaggini, F.; Orchard, M.; Fioraso-Cartier, L.; Cagnon, L.;Houngniou-Molango, S.; Gradia, A.; Duboux, G.; Merlot, C.; Heitz, F.; Szyndralewiez, C.; Page, P. First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J. Med. Chem. 2010, 53, 7715–7730; (b) Gaggini, F.; Laleu, B.; Orchard, M.; Fioraso-Cartier, L.; Cagnon, L; Houngninou-Molango, S.; Gradia, A.; Duboux, G.; Heitz, F.; Szyndralewiez, C.; Page, P. Design, synthesis and biological activity of original pyrazolo-pyrido-

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 82 of 99

diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. Bioorg. Med. Chem. 2011, 19, 6989–6999. (99) Kehrer, J. P.; Margolin, S. B. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol. Lett.1997, 90, 125–132. (100) Yehualaeshet, T.;O'Connor, R.; Begleiter, A.; Murphy-Ullrich, J. E.; Silverstein, R.; Khalil, N. A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat. Am. J. Respir. Cell Mol. Biol. 2000, 23, 204 –212. (101) Iyer, S. N.; Gurujeyalakshmi, G.; Giri, S. N. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J. Pharmacol. Exp. Ther. 1999, 291, 367–373. (102) Iyer, S. N.; Wild, J. S.; Schiedt, M. J.; Hyde, D. M.; Margolin, S. B.; Giri, S. N. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J. Lab. Clin. Med.1995, 125, 779–785. (103) Shetlar, M. R.; Shetlar, C. L. Effect of antifibrosis drug on the survival of keloid transplants in athymic mice. FASEB J. 1995, 9, A967. (104) Ammar, Y. A.; Ismail, M. M. F.; El-Sehrawi, H. M.; Noaman, E.; Bayomi, A. H.; Shawer, T. Z. Novel pirfenidone analogues: synthesis of pyridin-2-ones for the treatment of pulmonary fibrosis. Arch. Pharm. Chem. Life Sci. 2006, 339, 429–436.

ACS Paragon Plus Environment

Page 83 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(105) Giri, S. N.; Wang, Q.; Xie, Y.; Lango, J.; Morin, D.; Margolin, S. B.; Buckpitt, A. R. Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration. Biopharm. Drug Dispos. 2002, 23, 203-211. (106) Chen, J.; Liu, M. M.; Liu, B.; Chen, Z.; Li, Q. B.; Tao, L. J.; Hu, G. Y. Synthesis and structure– activity relationship of 5-substituent-2(1H)-pyridone derivatives as anti-fibrosis agents. Bioorg. Med. Chem. Lett. 2012, 22, 2300-2302. (107) Wu, L.; Liu, B.; Li, Q.; Chen, J.; Tao, L.; Hu, G. Design, synthesis and anti-fibrosis activity study of N1-substituted phenylhydroquinolinone derivatives. Molecules. 2012, 17, 1373-1387. (108) Lou, Q.; Meng, X.; Lao, Z.; Xuan, L.; Bai, J.; Hou, Q.; Hu, G.; Luo, R.; Tao, L.; Li, Z. Design, synthesis and antifibrotic activities of carbohydrate- modified 1-(substituted aryl)-5-trifluoromethyl2(1H) pyridones. Molecules. 2012, 17, 884-896. (109) Kossen, K.; Seiwert, S. D.; Serebryany, V.; Ruhrmund, D.; Beigelman, L.; Raveglia, L. F.; Vallese, S.; Bianchi, I.; Hu, T. Compounds and methods for treating inflammatory and fibrotic disorders. US Patent 20090318455A1, 2009. (110) Ma, Z.; Pan, Y.; Huang, W.; Yang, Y.; Wang, Z.; Li, Q.; Zhao, Y.; Zhang, X.; Shen, Z. Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents. Bioorg. Med. Chem. Lett. 2014, 24, 220–223. (111) Ueki, N.; Nakazato, M.; Ohkawa, T.; Ikeda, T.; Amuro, Y.; Hada, T.; Higashino, K. Excessive production of transforming growth-factor beta 1 can play an important role in the development of

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 84 of 99

tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim. Biophys. Acta. 1992, 1137, 189–196. (112) Park, J.; Kim, D. S.; Shim, T. S.; Lim, C. M.; Koh, Y. ; Lee, S. D.; Kim, W. S.; Kim, W. D.; Lee, J. S.; Song, K. S. Lung cancer in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 2001, 17, 1216–1219. (113) Aubry, M. C.; Myers, J. L.; Douglas, W. W.; Tazelaar, H. D.; Washington Stephens, T. L.; Hartman, T. E.; Deschamps, C.; Pankratz, V. S. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin. Proc. 2002, 77, 763–770. (113) Zhu, W.; Shen, J.; Li, Q.; Chen, J.; Chen, Z.; Liu, Z.; Hu, G. Synthesis, pharmacophores, and mechanism study of pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A. Arch. Pharm. Chem. Life Sci. 2013, 346, 654–666. (115) Lasky, J. Pirfenidone. IDrugs 2004, 7, 166-172. (116) Tao, L. J.; Hu, G. Y.; Tan, G. S. Antifibrosis pyridinone medicine and its preparing process. CN 1386737A, 2002. (117) Tao, L. J.; Zhang, J.; Hu, G. Y. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004, 29, 139-141. (118) Mirkovic, S.; Seymour, A. M.; Fenning, A.; Strachan, A.; Margolin, S. B.; Taylor, S. M.; Brown, L. Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats. Br. J. Pharmacol. 2002, 135, 961-968.

ACS Paragon Plus Environment

Page 85 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(119) Iyer, S. N.; Margolin, S. B.; Hyde, D. M.; Giri, S. N. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp. Lung Res.1998, 24, 119-132. (120) Chen, J.; Lu, M. M.; Liu, B.; Chen, Z.; Li, Q. B.; Tao, L. J.; Hu, G. Y. Synthesis and structure– activity relationship of 5-substituent-2(1H)-pyridone derivatives as anti-fibrosis agents. Bioorg. Med. Chem. Lett. 2012, 22, 2300–2302. (121) Xu, Q.; Jiang, X.; Zhu, W.; Chen, C.; Hu, G.; Li, Q. Synthesis, preliminary biological evaluation and 3D-QSAR study of novel 1,5-disubstituted-2(1H)-pyridone derivatives as potential anti-lung cancer agents. Arabian J. Chem. 2016, 9, 721-735. (122) Semen, K.O.; den Hartog, G. J.; Kaminskyy, D. V.; Sirota, T. V.; Maij, N. G. A. A.; Yelisyeyeva, O. P.; Bast, A. Redox modulation by amaranth oil in human lung fibroblasts. Nat. Prod. Chem. Res. 2013, 2, 1000122. (123) (a) den Hartog, G. J.; Qi, S.; van Tilburg, J. H.; Koek, G. H.; Bast, A. Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels: a new target in liver fibrosis. Eur. J. Pharmacol. 2014, 724, 140-144; (b) Qi, S.; den Hartog, G. J.; Bast, A. Superoxide radicals increase transforming growth factor-beta1 and collagen release from human lung fibroblasts via cellular influx through chloride channels. Toxicol. Appl. Pharmacol. 2009, 237, 111-118. (124) (a) Kaminskyy, D.; Subtel'na, I.; Zimenkovsky, B.; Karpenko, O.; Gzella, A.; Lesyk, R. Synthesis and evaluation of anticancer activity of 5-ylidene-4-aminothiazol-2(5H)-one derivatives,

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 86 of 99

Med. Chem. 2015, 11, 517-530; (b) Baell, J. B.; Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 2010, 53, 2719-2740; (c) Mendgen, T.; Steuer, C.; Klein, C. D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry. J. Med. Chem. 2012, 55, 743-753; (d) Hajduk, P. J.; Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 2007, 6, 211-219; (e) Forman, H. J.; Davies, K. J.; Ursini, F. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic. Biol. Med. 2014, 66, 24-35. (125) Kaminskyy, D.; den Hartog G. J.; Wojtyra, M.; Lelyukh, M.; Gzella, A.; Bast, A.; Lesyk, R. Antifibrotic and anticancer action of 5-ene amino/iminothiazolidinones. Eur. J. Med. Chem. 2016, 112, 180-195. (126) (a) Parrill, A. L.; Baker, D. L. Autotaxin inhibitors: a perspective on initial medicinal chemistry efforts. Expert Opin. Ther. Pat. 2010, 20, 1619−1625; (b) Lin, M. E.; Herr, D. R.; Chun, J. Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins Other Lipid Mediat. 2010, 91, 130−138. (127) Tager, A. M.; LaCamera, P.; Shea, B. S.; Campanella, G. S.; Selman, M.; Zhao, Z.; Polosukhin, V.; Wain, J.; Karimi-Shah, B. A.; Kim, N. D.; Hart, W. K.; Pardo, A.; Blackwell, T. S.; Xu, Y.; Chun,

ACS Paragon Plus Environment

Page 87 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

J.; Luster, A. D. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 2008, 14, 45−54. (128) (a) Ohta, H.; Sato, K.; Murata, N.; Damirin, A.; Malchinkhuu, E.; Kon, J.; Kimura, T.; Tobo, M.; Yamazaki, Y.; Watanabe, T.; Yagi, M.; Sato, M.; Suzuki, R.; Murooka, H.; Sakai, T.; Nishitoba, T.; Im, D. S.; Nochi, H.; Tamoto, K.; Tomura, H.; Okajima, F. Ki16425, a subtypeselective antagonist for EDG-family lysophosphatidic acid receptors. Mol. Pharmacol. 2003, 64, 994−1005; (b) Swaney, J. S.; Chapman, C.; Correa, L. D.; Stebbins, K. J.; Bundey, R. A.; Prodanovich, P. C.; Fagan, P.; Baccei, C. S.; Santini, A. M.; Hutchinson, J. H.; Seiders, T. J.; Parr, T. A.; Prasit, P.; Evans, J. F.; Lorrain, D. S. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br. J. Pharmacol. 2010, 160, 1699−1713; (c) Swaney, J. S.; Chapman, C.; Correa, L. D.; Stebbins, K. J.; Broadhead, A. R.; Bain, G.; Santini, A. M.; Darlington, J.; King, C. D.; Baccei, C. S.; Lee, C.; Parr, T. A.; Roppe, J. R.; Seiders, T. J.; Ziff, J.; Prasit, P.; Hutchinson, J. H.; Evans, J. F.; Lorrain, D.S. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J. Pharmacol. Exp. Ther. 2011, 336, 693−700; (d) Castelino, F. V.; Seiders, J.; Bain, G.; Brooks, S. F.; King, C. D.; Swaney, J. S.; Lorrain, D. S.; Chun, J.; Luster, A. D.; Tager, A. M. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 2011, 63, 1405−1415.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 88 of 99

(129) Qian, Y.; Hamilton, M.; Sidduri, A.; Gabriel, S.; Ren, Y.; Peng, R.; Kondru, R.; Narayanan, A.; Truitt, T.; Hamid, R.; Chen, Y.; Zhang, L.; Fretland, A. J.; Sanchez, R. A.; Chang, K. C.; Lucas, M.; Schoenfeld, R. C.; Laine, D.; Fuentes, M. E.; Stevenson, C. S.; Budd, D. C. Discovery of highly selective and orally active lysophosphatidic acid receptor‑1 antagonists with potent activity on human lung fibroblasts. J. Med. Chem. 2012, 55, 7920−7939. (130) (a) Rancoule, C.; Pradere, J. P.; Gonzalez, J.; Klein, J.; Valet, P.;Bascands, J. L.; Schanstra, J. P.; Saulnier-Blache, J. S. Lysophosphatidic acid-1-receptor targeting agents for fibrosis. Expert Opin. Invest. Drugs. 2011, 20, 657-667; (b) Budd, D. C.; Qian, Y. Development of lysophosphatidic acid pathway modulators as therapies for fibrosis. Future Med. Chem. 2013, 5, 1935-1952. (131) Sidduri, A.; Budd, D. C.; Fuentes, M. E.; Lambros, T.; Ren, Y.; Roongta, V.; Schoenfeld, R. C.; Gillespie, P.; Stevenson, C. S.; Truitt, T.; Qian, Y. Discovery of novel non-carboxylic acid 5-amino-4cyanopyrazole derivatives as potent and highly selective LPA1R antagonists. Bioorg Med. Chem. Lett. 2014, 24, 4450–4454. (132) Garneau-Tsodikova, S.; Thannickal, V. J. Protein kinase inhibitors in the treatment of pulmonary fibrosis. Curr. Med. Chem. 2008, 15, 2632-2640. (133) (a) Daniels, C. E.; Wilkes, M. C.; Edens, M.; Kottom, T. J.; Murphy, S. J.; Limper, A. H.; Leof, E. B. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J. Clin. Invest. 2004, 114, 1308-1316; (b) Aono, Y.; Nishioka, Y.; Inayama, M.; Ugai, M.; Kishi, J.; Uehara, H.; Izumi, K.; Sone, S. Imatinib as a novel antifibrotic

ACS Paragon Plus Environment

Page 89 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

agent in bleomycin-induced pulmonary fibrosis in mice. Am. J. Respir. Crit. Care Med. 2005, 171, 1279-1285;

(c) Chaudhary, N. I.; Schnapp, A.; Park, J. E. Pharmacologic differentiation of

inflammation and fibrosis in the rat bleomycin model. Am. J. Respir. Crit. Care Med. 2006, 173, 769776. (134) (a) Easton, J. B.; Houghton, P. J. mTOR and cancer therapy. Oncogene 2006, 25, 6436-6446; (b) Mota, A. Sirolimus: a new option in transplantation. Expert Opin. Pharmacother. 2005, 6, 479487; (c) Simler, N. R.; Howell, D. C.; Marshall, R. P.; Goldsack, N. R.; Hasleton, P. S.; Laurent, G. J.; Chambers, R. C.; Egan, J. J. The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats. Eur. Respir. J. 2002, 19, 1124-1127. (135) Laping, N. J.; Huet, S. TGF-β receptor kinase inhibitors for treatment of fibrosis. Smad Signal Transduction 2006, 5, 443-459. (136) (a) Hanke, J. H.; Gardner, J. P.; Dow, R. L.; Changelian, P. S.; Brissette, W. H.; Weringer, E. J.; Pollok, B. A.; Connelly, P. A. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 1996, 271, 695-701; (b) Vittal, R.; Horowitz, J. C.; Moore, B. B.; Zhang, H.; Martinez, F. J.; Toews, G. B.; Standiford, T. J.; Thannickal, V. J. Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury. Am. J. Pathol. 2005, 166, 367-375.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 90 of 99

(137) Son, J. Y.; Park, S. Y.; Kim, S. J.; Lee, S. J.; Park, S. A.; Kim, M. J.; Kim, S. W.; Kim, D. K.; Nam, J. S.; Sheen, Y. Y. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol. Cancer Ther. 2014, 13, 1704-1716. (138) Siddiqui, M. A.; Reddy, P. A. Small molecule JNK (c-Jun N-terminal kinase) inhibitors. J. Med. Chem. 2010, 53, 3005-3012. (139) Plantevin Krenitsky, V.; Nadolny, L.; Delgado, M.; Ayala, L.; Clareen, S. S.; Hilgraf, R.; Albers, R.; Hegde, S.; D'Sidocky, N.; Sapienza, J.; Wright, J.; McCarrick, M.; Bahmanyar, S.; Chamberlain, P.; Delker, S. L.; Muir, J.; Giegel, D.; Xu, L.; Celeridad, M.; Lachowitzer, J.; Bennett, B.; Moghaddam, M.; Khatsenko, O.; Katz, J.; Fan, R.; Bai, A.; Tang, Y. Shirley, M. A.; Benish, B. Bodine, T. Blease, K.; Raymon, H.; Cathers, B. E. Satoh, Y. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 1433–1438. (140) Cook, N. L. ; Romashkan, S. Why do we need a trial on the effects of testosterone therapy in older men? Clin. Pharmacol. Ther. 2011, 89, 29-31. (141) ClinicalTrials.gov. A study to characterize the safety, PK and biological activity of CC-930 in idiopathic pulmonary fibrosis (IPF). http://clinicaltrials.gov/ct2/show/NCT01203943 (access May 20, 2016). (142) Deleuze-Masquefa, C.; Moarbess, G.; Khier, S.; David, N.; Gayraud-Paniagua, S.; Bressolle, F.; Pinguet, F.; Bonnet, P. A. New imidazo[1,2-a]quinoxaline derivatives: Synthesis and in vitro activity against human melanoma. Eur. J. Med. Chem. 2009, 44, 3406-3411.

ACS Paragon Plus Environment

Page 91 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(143) Li, B.; Cociorva, O. M.; Nomanbhoy, T.; Weissig, H.; Li, Q.; Nakamura, K.; Liyanage, M.; Zhang, M. C.; Shih, A. Y.; Aban, A.; Hu, Y.; Cajica, J.; Pham, L., Kozarich, J. W.; Shreder, K. R. Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 5217–5222. (144) (a) Wynn, T. A.; Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 2012, 18, 1028-1040; (b) Bartram, U.; Speer, C. P. The role of transforming growth factor beta in lung development and disease. Chest. 2004, 125, 754-765.; (c) Strieter, R. M.; Mehrad, B. New mechanisms of pulmonary fibrosis. Chest. 2009, 136, 1364-1370; (d) Arribillaga, L.; Dotor, J.; Basagoiti, M.; Riezu-Boj, J. I.; Borrás-Cuesta, F.; Lasarte, J. J.; Sarobe, P.; Cornet, M. E.; Feijoó, E. Therapeutic effect of a peptide inhibitor of TGF-β on pulmonary fibrosis. Cytokine. 2011, 53, 327-333; (e) Khasnis, A. A.; Calabrese, L. H. Tumor necrosis factor inhibitors and lung disease: a paradox of efficacy and risk. Semin. Arthritis Rheum. 2010, 40, 147-163. (145) Zhu, J.; He, L.; Ma, L.; Wei, Z; He, J.; Yang, Z.; Pu, Y.; Cao, D.; Wu, Y.; Xiang, M.; Peng, A.; Wei, Y.; Chen, L. Synthesis and biological evaluation of 4-oxoquinoline-3-carboxamides derivatives as potent anti-fibrosis agents. Bioorg. Med. Chem. Lett. 2014, 24, 5666–5670. (146) Schwiebert, E.; Streiff, J.; Dixon, J.; Gao, H.; Ritchie, J. P.; Seales, E. C.; Mai, D. Coumarin derivatives and methods of use in treating hyperproliferative diseases. U.S. Patent 20160038475 A1, 2016.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 92 of 99

(147) (a) Gilbert, F.; Robert, G. J.; Jonathan, L.;Maurice, L. R.;Fletcher, S. R. Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists). U.S. Patent 20160039807 A1, 2016. (b) Gilbert, F.; Robert, G. J.; Jonathan, L.; Maurice, L. R.; Fletcher, S. R. Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders. U.S. Patent 20140121204 A1, 2014. (148) Stadlwieser, J.; Schmidt, B.; Bernsmann, H.; Dunkern, T.; Benediktus, E.; Pahl, A.; Hussong, R.; Nimz, O.; Mueller, M.; Viertelhaus, M. Methylpyrrolopyrimidinecarboxamides. U.S. Patent 20150073001, 2015. (149) (a) Hood, J.; Kumar, S. K. C.; Wallace, D. M. 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof. U.S. Patent 20150150862, 2015. (b) Hood, J.; Kumar, S. K. C.; Wallace, D. M. 1Hpyrazolo[3,4-b]pyridines and therapeutic uses thereof. U.S. Patent 20130296302, 2013. (150) Notte, G. Apoptosis signal-regulating kinase inhibitors. U.S. Patent 20140179663 A1, 2014. (151) Allegretti, M.; Cesta, M. C.; Bertini, R.; Mosca, M.; Colotta, F. 2-phenylpropionic acid derivatives and pharmaceutical compositions containing them. U.S. Patent 20120004264 A1, 2012. (152) Moriconi, A.; Allegretti, M.; Cesta, M. C.; Bertini, R.; Bizzarri, C.; Colotta, F. 2-aryl-acetic acids, their derivatives and pharmaceutical compositions containing them. U.S. Patent 20110195967 A1, 2011. (153) Holsinger, L. Inhibitors of cathepsinb. U.S. Patent 20090203629 A1, 2009.

ACS Paragon Plus Environment

Page 93 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(154) Kossen, K.; Seiwert, S. D.; Serebryany, V.; Ruhrmund, D.; Beigelman, L.; Raveglia, L. F.; Vallese, S.; Bianchi, I.; Hu, T. Compounds and methods for treating inflammatory and fibrotic disorders. U.S. Patent 20090318455 A1, 2009. (155) Gant, T. G.; Sarshar, S. Substituted n-aryl pyridinones. U.S. Patent 20080319026 A1, 2008. (156) Hart, B.;Axon, J. R.; Chakravarty, S.; Murphy, A.; Mcenroe, Glenn. Heterocyclic inhibitors of TGF-β. WO 2006105063 A1, 2006. (157) Levin, J.; Li, Z.; Diamantidis, G.; Lovering, F.; Wang, W.; Condon, J.; Lin, Y.- I.; Skotnicki, J.; Park, K. Beta-sulfonamide hydroxamic acid inhibitors of tace/matrix metalloproteinase. U.S. Patent 20060211730 A1, 2006. (158) (a) Nanthakumar, C. B.; Hatley, R. J. D.; Lemma, S.; Gauldie, J.; Marshall, R. P.; Macdonald, S. J. F. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat. Rev. Drug Discov. 2015, 14, 693–720; (b) Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem.2005, 48, 6523–6543. (159) (a) Regulatory watch: First drug for idiopathic pulmonary fibrosis approved in Japan. Nat. Rev. Drug Discov. 2008, 7, 966-967; (b) Macías-Barragán, J.; Sandoval-Rodríguez, A.; Navarro-Partida, J.; Armendáriz-Borunda, J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair. 2010, 3, 16; (c) Han, Y. J.; Kim, H. Y.; Lim, K. Y.; Hwangbo, B.; Lee, J. S. A phase II study of nintedanib in patients with relapsed small cell lung cancer. Lung Cancer. 2016, 96, 108-112.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 94 of 99

(160) Korfei, M.; Skwarna, S.; Henneke, I.;MacKenzie, B.; Klymenko, O.; Saito, S.; Ruppert, C.; Beck, D. V. D.; Mahavadi, P.; Klepetko, W.; Bellusci, S.; Crestani, B.; Pullamsetti, S. S.; Fink, L.; Seeger, W.; Krämer, O. H.; Guenther, A. Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis. Thorax 2015, 70, 1022-1032. (161) (a) Marco-Contelles, J.; Soriano, E. The medicinal chemistry of hybrid-based drugs targeting multiple sites of action. Curr. Top Med. Chem. 2011, 11, 2714-2715; (b) Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. J.; Fraga, C. A. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr. Med. Chem. 2007, 14, 1829-1852; (c) Biot, C.; Chibale, K. Novel approaches to antimalarial drug discovery. Infect. Disord. Drug Targets 2006, 6, 173-204; (d) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Natural product hybrids as new leads for drug discovery. Angew Chem. Int. Ed.Engl. 2003, 42, 3996-4028. (162) (a) Ley, B.; Brown, K. K.; Collard, H. R. Molecular biomarkers in idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 307, L681-L691; (b) Ye, N.; Ding, Y.; Wild, C.; Shen, Q.; Zhou, J. Small molecular inhibitors targeting activator protein 1 (AP-1). J. Med. Chem. 2014, 57, 6930-6948; (c) Jarman, E. R.; Khambata, V. S.; Cope, C.; Jones, P.; Roger, J.; Ye, L. Y.; Duggan, N.; Head, D.; Pearce, A; Press, N. J.; Bellenie, B.; Sohal, B.; Jarai, G. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am. J. Respir. Cell Mol. Biol. 2014, 50, 158-169; (d) Vij, R.; Noth, I. Peripheral blood biomarkers in idiopathic pulmonary fibrosis. Transl. Res. 2012, 159, 218-227.

ACS Paragon Plus Environment

Page 95 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(163) Orens, J. B.; Estenne, M.; Arcasoy, S.; Conte, J. V.; Corris, P.; Egan, J. J.; Egan, T.; Keshavjee, S.; Knoop, C.; Kotloff, R.; Martinez, F. J.; Nathan, S.; Palmer, S.; Patterson, A.; Singer, L.; Snell, G.; Studer, S.; Vachiery, J. L.; Glanville, A. R. International guidelines for the selection of lung transplant candidates: 2006 updates-a consensus report from the pulmonary scientific council of the international society for heart and lung transplantation. J. Heart. Lung. Transplant. 2006, 25, 745755. (164) Weill, D.; Benden, C.; Corris, P. A.; Dark, J. H.; Davis, R. D.; Keshavjee, S.; Lederer, D. J.; Mulligan, M. J.; Patterson, G. A.; Singer, L. G.; Snell, G. I.; Verleden, G. M.; Zamora, M. R.; Glanville, A. R. A consensus document for the selection of lung transplant candidates: 2014-an updates from the pulmonary transplantation council of the international society for heart and lung transplantation. J. Heart. Lung. Transplant. 2015, 34, 1-15. (165) Thabut, G.; Christie, J. D.; Ravaud, P.; Castier, Y.; Dauriat, G.; Jebrak, G.; Fournier, M.; Lesèche, G.; Porcher, R.; Mal, H. Survival after bilateral versus single-lung transplantation for idiopathic pulmonary fibrosis. Ann. Intern. Med. 2009, 151, 767-774. (166) Chauhan, D.; Karanam, A. B.; Merlo, A.; Bozzay, T.; Zucker, M. J.; Seethamraju, H.; Shariati, N.; Russo, M. J. Post-transplant survival in idiopathic pulmonary fibrosis patients concurrently listed for single and double lung transplantation. J. Heart. Lung. Transplant. 2016, 35, 657-660. (167) Bennett, D.; Fossi, A.; Bargagli, E.; Refini, R. M.; Pieroni, M.; Luzzi, L.; Ghiribelli, C.; Paladini, P.; Voltolini, L.; Rottoli. P. Mortality on the waiting list for lung transplantation in patients

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 96 of 99

with idiopathic pulmonary fibrosis: a single-centre experience. Lung 2015, 193, 677-681. (168) He, W.-X.; Yang, Y.-L.; Song, N.; Liu, M.; Zhang, P.; Fan, J.; Jiang, G.-N. Outcomes of Chinese patients with end-stage pulmonary disease while awaiting lung transplantation: a singlecenter study. Chin. Med. J. 2016, 129, 3-7. (169) Kenn, K.; Gloeckl, R.; Behr, J. Pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis-a review. Respiration 2013, 86, 89-99. (170) Nishiyama, O.; Kondoh, Y.; Kimura, T.; Kato, K.; Kataoka, K.; Ogawa, T.; Watanabe, F.; Arizono, S.; Nishimura, K.; Taniguchi, H. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology 2008, 13, 394-399. (171) Vainshelboim, B.; Oliveira, J.; Fox, B. D.; Soreck, Y.; Fruchter, O.; Kramer, M. R. Long-term effects of a 12-week exercise training program on clinical outcomes in idiopathic pulmonary fibrosis. Lung 2015, 193, 345-354. (172) Swigris, J. J.; Fairclough, D. L.; Morrison, M.; Make, B.; Kozora, E.; Brown, K. K.; Wamboldt, F. S. Benefits of pulmonary rehabilitation in idiopathic pulmonary fibrosis. Respir. Care. 2011, 56, 783-789. (173) Gaunaurd, I. A.; Gómez-Marín, O. W.; Ramos, C. F.; Sol, C. M.; Cohen, M. I.; Cahalin, L .P.; Cardenas, D. D.; Jackson, R. M. Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis completing a pulmonary rehabilitation program. Respir. Care. 2014, 59, 1872-1879.

ACS Paragon Plus Environment

Page 97 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

(174) Vainshelboim, B.; Oliveira, J.; Yehoshua, L.; Weiss, I.; Fox, B. D.; Fruchter, O.; Kramer, M. R. Exercise training-based pulmonary rehabilitation program is clinically beneficial for idiopathic pulmonary fibrosis. Respiration 2014, 88, 378-388. (175) Jackson, R. M.; Gómez-Marín, O. W.; Ramos, C. F.; Sol, C. M.; Cohen, M. I.; Gaunaurd, I. A.; Cahalin, L .P.; Cardenas, D. D. Exercise limitation in IPF patients: a randomized trial of pulmonary rehabilitation. Lung 2014, 192, 367-376. (176) Lee. J. S.; Ryu, J. H.; Elicker, B. M.; Lydell, C. P.; Jones, K. D.; Wolters, P. J.; King, T. E. Jr.; Collard, H. R. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care. Med. 2011, 184, 1390-1394. (177) Raghu, G.; Amatto, V. C.; Behr, J.; Stowasser, S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur. Respir. J. 2015, 46, 1113-1130. (178) King, C.; Nathan, S. D. Identification and treatment of comorbidities in idiopathic pulmonary fibrosis and other fibrotic lung diseases. Curr. Opin. Pulm. Med. 2013, 19, 466-473. (179) Schiza, S.; Mermigkis, C.; Margaritopoulos, G. A.; Daniil, Z.; Harari, S.; Poletti, V.; Renzoni, E. A.; Torre, O.; Visca, D.; Bouloukaki, I.; Sourvinos, G.; Antoniou, K. M. Idiopathic pulmonary fibrosis and sleep disorders: no longer strangers in the night. Eur. Respir. Rev. 2015, 24, 327-339. (180) Pihtili, A.; Bingol, Z.; Kiyan, E.; Cuhadaroglu, C.; Issever, H.; Gulbaran, Z. Obstructive sleep apnea is common in patients with interstitial lung disease. Sleep. Breath. 2013, 17, 1281-1288. (181) Mermigkis, C.; Bouloukaki, I.; Antoniou, K.; Papadogiannis, G.; Giannarakis, I.; Varouchakis,

ACS Paragon Plus Environment

Journal of Medicinal Chemistry

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 98 of 99

G.; Siafakas, N.; Schiza, E. S. Obstructive sleep apnea should be treated in patients with idiopathic pulmonary fibrosis. Sleep. Breath. 2015, 19, 385-391.

ACS Paragon Plus Environment

Page 99 of 99

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Table of Content graphic

ACS Paragon Plus Environment