Identification and Optimization of a Series of Non-Steroidal

Chapter 5

Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1240.ch005

Identification and Optimization of a Series of Non-Steroidal Trifluoromethylcarbinol Glucocorticoid Receptor Agonists Christian Harcken*,1 and Hossein Razavi2 1Department of Immunology and Respiratory Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06778, United States 2Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06778, United States *E-mail: [email protected].

Steroidal glucocorticoids (GCs) are among the most used classes of anti-inflammatory drugs. However, their chronic use is severely limited by deleterious side effects such as GC-induced osteoporosis. A series of non-steroidal trifluoromethylcarbinol glucocorticoid receptor (GR) agonists was identified from literature-known nuclear hormone receptor binder motifs. The series was successively optimized for potency, selectivity, and in vivo activity through rational design. Compounds with reduced GR-related side effects were identified empirically, ultimately the drug-like properties of these compounds were optimized resulting in the identification of the clinical candidate BI 653048.

Introduction Glucocorticoids (GCs) are among the most widely used anti-inflammatory drugs. More than 60 years ago, cortisone (1) was first used for the treatment of rheumatoid arthritis (Figure 1) (1). Soon thereafter, the first synthetic steroidal glucocorticoids were developed: dexamethasone (2) and prednisolone (3) are still widely used in clinical practice today. At the time, these treatments were hailed as the “cure” for inflammatory and auto-immune diseases; however, a © 2016 American Chemical Society Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


plethora of side effects upon their chronic use were soon discovered. These undesired effects included weight gain, fat redistribution, obesity, GC-induced diabetes, GC-induced osteoporosis, cataracts, hypertension and CNS effects (2). In particular, GC-induced diabetes and osteoporosis severely limited the suitable doses and durations for the chronic administration of glucocorticoids (3). Thus, the discovery of a GC with substantially reduced side effects is highly desirable and has led to numerous drug discovery and development programs. However, a proof of clinical concept for a therapeutically beneficial GC with diminished side effects remains elusive to this day.

Figure 1. Steroidal Glucocorticoids (GCs).

GCs elicit their effects through interaction with the glucocorticoid receptor (GR) — a nuclear hormone receptor (NHR) and transcription factor. GCs function as GR agonists. Two distinct functional mechanisms for GR agonists have been proposed (4). Upon binding of a GC to the cytosolic GR, a receptor-ligand complex forms that can dimerize, translocate to the nucleus and directly bind to glucocorticoid response elements (GREs) on the DNA resulting in the transcriptional up-regulation of selected genes. This direct activation of transcription has been termed “transactivation”. Alternatively, the receptor-ligand complex can translocate to the nucleus as a monomer and bind to transcription factors such as nuclear factor κB (NFκB) and activating protein 1 (AP1), thereby, impeding their activities and leading to the down-regulation of gene expression. This indirect suppression of transcription has been termed “transrepression”. Originally, it was hypothesized that transactivation was responsible for the majority of the undesired GC side effects while transrepression mediated their desired anti-inflammatory effects. The predominant approach for the discovery of a GC with reduced side effects has been to achieve functional selectivity or “dissociation” between these two pathways. However, during the past decade, it has become increasingly clear that the GR’s actions are more complex and that the concept of achieving reduced side effects based on functional dissociation may be too simplistic and does not account for the effects of negative GREs (i.e., DNA-binding-mediated direct transrepression), non-genomic effects through membrane bound GR and post-transcriptional effects, or the existence of GRα/β isoforms (5, 6). Additionally, many steroidal GCs elicit unwanted side effects by modulating other NHRs such as the mineralocorticoid receptor (MR) and progesterone receptor (PR). Hence, sufficient selectivity over these related receptors is a requirement for reducing off-target side effects. 172

Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Lead Identification


Schering AG (now Bayer-Schering) identified a non-steroidal trifluoromethylcarbinol series of GCs that is presumed to be derived from the androgen receptor antagonist bicalutamide (4; Figure 2) (7). Compound 5 is an example of an early Schering GR agonist (GR IC50 8 nM) (8) that has demonstrated in vitro and in vivo anti-inflammatory activity (9). However, this compound suffered from low selectivity and poor pharmacokinetic properties. At Boehringer Ingelheim (BI), we found that replacement of the amide linkage in 5 with alkyl linkers retained GR binding activity and led to the discovery of a novel class of compounds (10). The SAR showed that a methylene linker as in 6 was the optimal linker length for retaining GR binding affinity (GR IC50 610 nM).

Figure 2. Origin of Trifluoromethylcarbinol Glucocorticoids.

In general, compounds in this scaffold were synthesized through Friedel-Crafts alkylation of an appropriately substituted arene 7, followed by reduction and glycol cleavage of the product 8, and addition of the A-ring moiety to the intermediate trifluoromethylketone 9 (Scheme 1). Docking studies using a GR homology model showed that 6 was bound to the GR ligand-binding domain with its left-hand side (i.e., the phenyl ring) occupying the steroid A-ring pocket, while the methoxyfluorophenyl group resided in the steroid D-ring pocket. Increased steric bulk of the A-ring moiety improved GR binding affinity substantially such as in compound 10 (GR IC50 55 nM); however, this compound showed only marginal agonist activity in a cellular assay (IL-6 IC50 280 nM, 60% maximum efficacy vs. prednisolone) (11). Modelling studies suggested that the incorporation of a hydrogen bond acceptor (HBA), which would mimic the steroid A-ring carbonyl group should improve potency. The SAR of various substitution patterns on the left-hand side phenyl ring (i.e., the A-ring mimetic) led to compound 11 that showed potent GR binding activity (GR IC50 17 nM), moderate NHR selectivity (PR IC50 140 nM, MR IC50 320 nM) and partial agonism in a cellular assay (IL-6 IC50 20 nM, 60% maximum efficacy vs. prednisolone). 173



Scheme 1. First-Generation Synthesis Route

It is interesting to note that only the combination of a HBA (e.g., CN) and a lipophilic substituent (e.g., Cl) on the left-hand side phenyl ring was able to strike the right balance of properties to achieve cellular activity. Compound 11 showed low aqueous solubility and low metabolic stability that precluded its evaluation in vivo; nevertheless, it represented a novel class of non-steroidal GR agonists.

Potency Optimization Due to the apparent dramatic effect of the left-hand side substitution on agonist activity, we screened a variety of heterocyclic ring systems as A-ring mimetics (12). One of the preferred ring systems identified was the quinolone in compounds such as 12a (Figure 3). These compounds were synthesized using a second-generation route: starting from the addition of an appropriately substituted organometallic reagent such as 14 to the trifluoromethylenone 13, a shorter synthesis of the key trifluoromethylketones such as 9 was achieved (Scheme 2). The ketone 9 was transformed to the corresponding epoxide 15 using sulfur ylide chemistry. The final compound 12a was synthesized by nucleophilic opening of the epoxide with quinolone. This route was later modified to allow the preparation of enantiopure compounds by using epoxide (R)-15 that was synthesized in three steps through a chiral sulfoxide addition to provide intermediate (R)-16, separation of diastereomers, reduction to thioether (R)-17, and cyclization (Scheme 3) (13). Most of the GR activity in the trifluoromethylcarbinol series resides in the (R)-enantiomers. Compound 12a retained potent binding affinity (GR IC50 10 nM), moderate selectivity (PR IC50 470 nM, MR IC50 120 nM), and agonist cellular activity (IL-6 IC50 20 nM, 82% maximum efficacy). The right-hand side SAR revealed that a hydroxyl group at the C-2 position of the phenyl ring provided the highest agonist efficacy while a C-5 hydroxy group had a deleterious effect. The phenol analog 12b showed almost full transrepression efficacy (IL-6 IC50 6 nM, 92% maximum efficacy); however, this translated to only partial efficacy in an acute in vivo mouse model of TNF-α production 174



(55% inhibition of TNF-α at 10 mg/kg) (14). Further optimization to compounds such as 18 did not lead to a significant improvement of the in vivo profile (58% inhibition of TNF-α at 10 mg/kg). Due to these challenges, we turned to a different heterocyclic ring system.

Figure 3. Heteroaryl A-Ring Mimetics.

Scheme 2. Second-Generation Synthesis Route 175 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


We had previously identified the indole ring as a left-hand side replacement in our survey of heterocyclic ring systems. Compounds such as 19 had displayed potent GR binding (GR IC50 22 nM), moderate selectivity (PR IC50 290 nM, MR IC50 380 nM), and agonist cellular activity (IL-6 IC50 7 nM, 87% maximum efficacy) (15). A systematic SAR investigation on the indole ring system revealed a number of trends. In particular, it was discovered that the space available for substitution at the C-4 and C-7 positions was limited. In fact, substitutions at these positions led to lower agonist activity, and upon further increase of the substituents’ size, binding affinity was ultimately lost. Due to the proximity of the C-5 and C-6 positions to the Arg611/Glu570 pair in the GR binding pocket, substitution in these positions with an HBA should be beneficial for activity. Since unsubstituted indoles are electron rich and prone to metabolism, electron-withdrawing groups (EWG) such as CN that satisfied the HBA requirement appeared to be ideal substituents. Indeed, 5-CN and 6-CN substituted indoles showed good agonist activity and NHR selectivity. For instance, 6-cyanoindole 20 retained potent binding (GR IC50 14 nM), moderate selectivity (PR IC50 400 nM, MR IC50 440 nM) and agonist cellular activity (IL-6 IC50 14 nM, 91% maximum efficacy). The SAR of the right-hand side (D-ring mimetic) revealed that the selectivity could be further improved by introducing bulky substitution at the C-5 position as in the sulfonyl dihydrobenzofuran 21. These compounds showed potent GR affinity (GR IC50 6 nM) with >100-fold selectivity over MR and PR while maintaining moderate agonist activity (IL-6 IC50 100 nM). Thus, to impart potent agonist activity and NHR selectivity, a combination of 5-CN-indole A-ring and 5-sulfonyl-substituted dihydrobenzofuran D-ring mimetics was synthesized: Substituted indole analog (R)-22 (GR IC50 2 nM, MR IC50 230 nM, PR IC50 750 nM, IL-6 IC50 28 nM, 88% maximum efficacy) showed potent acute in vivo anti-inflammatory effects (97% inhibition of TNF-α production at 3 mg/kg). However, despite moderate to good mouse PK properties (4 mL/min/kg clearance, 0.9 L/kg VSS, 26% bioavailability; dosed at 1 mg/kg iv and 30 mg/kg po), the efficacy in the acute mouse model only translated to partial inhibitory effects in a chronic mouse model of collagen induced-arthritis (CIA) (45% maximum inhibition of disease score) (16).

Scheme 3. Enantiopure Synthesis Route 176 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


An alternative way of improving upon the profile of indoles like 19 was the incorporation of an additional ring nitrogen atom to form azaindoles (17). The systematic SAR exploration of all possible azaindole isomers revealed that the 5and 6-azaindole moieties not only increased potency, but also imparted further improvement in NHR selectivity. These compounds were synthesized using a third-generation synthesis route (Scheme 4). The key epoxide intermediate (R)15 was converted to the corresponding alkyne (S)-23 which was treated with an appropriately substituted and protected amino pyridine (e.g., iodopyridine 29) in a Sonagashira coupling followed by cyclization to yield the desired compounds such as (R)-24a. The base-mediated cyclization process used in this synthesis was developed in our labs and was a significant improvement over the literature-known processes (18). Compound (R)-24b was the first compound from this scaffold that showed dexamethasone-like potency (GR IC50 2 nM, IL-6 IC50 3 nM, 93% maximum efficacy) with greater than 100-fold selectivity over MR and PR (Figure 4). This compound demonstrated acceptable PK properties in rat (49 mL/min/kg clearance, 7.6 L/kg VSS, 48% bioavailability; dosed at 5 mg/kg iv and 30 mg/kg po) and potent acute anti-inflammatory effects in vivo (ED50 < 0.3 mg/kg for TNFα inhibition in mouse) that translated into dose-responsive efficacy in a chronic CIA mouse model. The compound inhibited disease progression approximately equipotent to prednisolone (daily dosing of 30 mg/kg of (R)-24b resulted in 92% inhibition as assessed by the arthritic score AUC compared to 77% with 30 mg/kg of prednisolone).

Dissociation Optimization Previously discussed compounds 12b, (R)-22 and (R)-24b showed a partial dissociation profile, since they were dissociated in a cellular transactivation assay with a direct read-out such as a MMTV reporter gene assay (19) but not in a functional aromatase transactivation assay (20). For example, (R)-24b was dissociated based on reduced potency and maximum efficacy in the MMTV assay (IC50 80 nM, maximum efficacy 30%), but did not show a dissociated profile in the aromatase assay (IC50 11 nM, 84% maximum efficacy) as compared to the transrepression activity (IL-6 IC50 3 nM, maximum efficacy 93%). To assess how this partially dissociated profile of (R)-24b would translate into in vivo dissociation, the compound and prednisolone were dosed in healthy mice for 5 w, and their metabolic side effect profile (e.g., body fat content, triglyceride, free fatty acid (FFA) and insulin levels) at equi-efficacious doses was analyzed. Body fat increase and increased insulin secretion were significantly reduced for (R)-24b as compared to prednisolone; however, FFA and triglyceride increases were comparable to prednisolone. Thus for the first time in this series, a partially dissociated in vitro profile translated to an in vivo reduction in metabolic side effects. Unfortunately, this in vivo dissociated profile did not extend to bone dissociation since micro-CT analysis showed that (R)-24b did not reduce GCinduced osteoporosis when compared to prednisolone. We were also able to achieve a comparable balance of potency, selectivity and partial dissociation by exploiting an induced D-ring binding pocket with related 177



compounds such as biaryl (R)-25 (IL-6 IC50 20 nM, 78% maximum efficacy; 85% inhibition in CIA model at 100 mg/kg) (17), or by subtle modifications of the central alkyl carbinol group as in t-butyl analogue (R)-26 (IL-6 IC50 27 nM, 76% maximum efficacy; 82% inhibition in CIA model at 100 mg/kg) (21).

Figure 4. Azaindole Glucocorticoids.

Scheme 4. Third-Generation Synthesis Route 178 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Bone Dissociation To assess the potential of the compounds for reduced bone side effects, we tested their ability to suppress osteocalcin (OC) production (22). A retrospective analysis of historical compounds revealed that partial agonist compounds (with 2000 nM, CYP3A4 IC50 2 µM). Therefore, we used the morpholinyl substituted 6-azaindole A-ring to re-investigate the D-ring SAR. Substitution with EWG at C-2 of the phenyl D-ring mimetic further increased maximum agonist efficacy, but provided reduced hERG and CYP inhibition such as in 32 (IL-6 IC50 4 nM, 95% maximum efficacy, hERG IC50 20 µM, CYP3A4 IC50 3 µM). The combination of these pharmacophores ultimately resulted in a panel of compounds that balanced all the desired properties. (R)-33 (BI 653048) was identified as the preferred combination from this exercise. This compound displayed a favorable selectivity profile, potent transrepression activity with partial agonism (IL-6 IC50 23 nM, 88% maximum efficacy), the desired degree of in vitro dissociation (MMTV maximum efficacy 33%, osteocalcin maximum efficacy 39%), reduced DDI potential (CYP3A4 IC50 8 µM), good metabolic stability (11% Qh HLM), and no risk of potential arrhythmia (hERG IC50 > 30 µM). Solely the aqueous solubility remained low (5 µg/mL at pH 6.8); however, a solid form with excellent dissolution properties was identified. For reasons that were poorly understood, this compound showed a species-difference in GR affinity. For example, the compound was significantly less potent in mouse in vitro assays, which precluded its profiling in our established mouse inflammation models. However, in a rat CIA model, the compound showed good potency (ED50 14 mg/kg). (R)-33 demonstrated acceptable safety margins in rat and dog pre-clinical safety pharmacology and toxicology studies and advanced to clinical trials in humans. Clinical data from a phase I proof-of-concept study will be disclosed in the near future.

Figure 5. Substituted Azaindole Glucocorticoids. 180 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

During the pre-clinical development phase, a more efficient route for the synthesis of (R)-33 was devised by Process Chemistry that improved upon the 17-step Medicinal Chemistry route, which was based on the third-generation synthesis route (Scheme 4). Significant optimization for the development of this scalable route will be discussed in the next chapter.


Conclusions In conclusion, a series of non-steroidal trifluoromethylcarbinol glucocorticoid receptor (GR) agonists was identified from literature-known nuclear hormone receptor binder motifs. The series was successively optimized for potency, selectivity, and in vivo activity through rational design. Compounds with reduced GR-related side effects were identified empirically, ultimately the drug-like properties of these compounds were optimized resulting in the identification of the clinical candidate BI 653048.

References 1.

2. 3. 4. 5. 6.

7.

8.

9.

Buttgereit, F.; Saag, K. G.; Cutolo, M.; da Silva, J. A. P.; Bijlsma, J. W. J. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis. Scand. J. Rheumatol. 2005, 34, 14–21. Schäcke, H.; Döcke, W.-D.; Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol. Ther. 2002, 96, 23–43. Weinstein, R. S. Glucocorticoid-induced bone disease. N. Engl. J. Med. 2011, 365, 62–70. Adcock, I. M. Molecular mechanisms of glucocorticosteroid actions. Pulm. Pharmacol. Ther. 2000, 13, 115–126. Clark, A. R.; Belvisi, M. G. Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor. Pharmacol. Ther. 2012, 134, 54–67. Newton, R.; Holden, N. S. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol. Pharmacol. 2007, 72, 799–809. He, Y.; Yin, D.; Perera, M.; Kirkovsky, L.; Stourman, W.; Dalton, J. T.; Miller, D. D. Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor. Eur. J. Med. Chem. 2002, 37, 619–634. GR, PR and MR binding assays were performed in a fluorescence polarization format that measures competition for binding to the nuclear receptor between a test compound and a fluorescently labeled receptor ligand. Schäke, H.; Schottelius, A.; Döcke, W. D.; Strehlke, P.; Jaroch, S.; Schmees, N.; Rehwinkel, H.; Hennekes, H.; Asadullah, K. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227–232. 181



10. Kuzmich, D.; Kirrane, T.; Proudfoot, J.; Bekkali, Y.; Zindell, R.; Beck, L.; Nelson, R.; Shih, C.-K.; Kukulka, A. J.; Paw, Z.; Reilly, P.; Deleon, R.; Cardozo, M.; Nabozny, G.; Thomson, D. Identification of dissociated nonsteroidal glucocorticoid receptor agonists. Bioorg. Med. Chem. Lett. 2007, 17, 5025–5031. 11. The IL-6 assay measures the ability of test compounds to inhibit the production of IL-6 by human foreskin fibroblasts following stimulation by IL-1 in vitro. The maximum inhibition by the test compound is compared to prednisolone at 2 µM which is set to 100%. 12. Regan, J.; Lee, T. W.; Zindell, R. M.; Bekkali, Y.; Bentzien, J.; Gilmore, T.; Hammach, A.; Kirrane, T. M.; Kukulka, A. J.; Kuzmich, D.; Nelson, R. M.; Proudfoot, J. R.; Ralph, M.; Pelletier, J.; Souza, D.; Zuvela-Jelaska, L.; Nabozny, G.; Thomson, D. S. Quinol-4-ones as steroid A-Ring mimetics in nonsteroidal dissociated glucocorticoid agonists. J. Med. Chem. 2006, 49, 7887–7896. 13. Lee, T. W.; Proudfoot, J. R.; Thomson, D. S. A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol. Bioorg. Med. Chem. Lett. 2006, 16, 654–657. 14. The model measures the ability of a single dose of test compound to inhibit the production of serum TNF-α after stimulation with LPS in Balb/c mice. 15. Betageri, R.; Gilmore, T.; Kuzmich, D.; Kirrane, T. M.; Bentzien, J.; Wiedenmeyer, D.; Regan, J.; Kukulka, A. J.; Fadra, T. N.; Nelson, R. M.; Zuvela-Jelaska, L.; Souza, D.; Pelletier, J.; Proudfoot, J.; Dinallo, R.; Panzenbeck, M.; Torcellini, C.; Lee, H.; Pack, E.; Harcken, C.; Nabozny, G.; Thomson, D. S. Non-steroidal Dissociated Glucocorticoid Agonists: lndoles as A-Ring Mimetics and Function-regulating Pharmacophores. Bioorg. Med. Chem. Lett. 2011, 21, 6842–6851. 16. In this model B10.RIII mice immunized with type II collagen are scored daily for paw swelling for 5 weeks. 17. Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.; Pack, E. J., Jr.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.; Torcellini, C.; Nabozny, G. H.; Thomson, D. S. Nonsteroidal Dissociated Glucocorticoid Agonists Containing Azaindoles as Steroid A-Ring Mimetics. J. Med. Chem. 2010, 53, 6681–6698. 18. Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. A General and Efficient Synthesis of Azaindoles and Diazaindoles. Synlett 2005, 3121–3124. 19. The MMTV transactivation assay measures the ability of test compounds to activate MMTV promoter in HeLa cells stably transfected with MMTV luciferase construct. The maximum activation by the test compound is compared to prednisolone at 2 µM which is set to 100%. 20. The aromatase assay measures the ability of test compounds to induce aromatase activity in human foreskin fibroblasts. The maximum activation by the test compound is compared to prednisolone at 2 µM which is set to 100%. 182



21. Razavi, H.; Riether, D.; Harcken, C.; Bentzien, J.; Dinallo, R. M.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra-Khan, T. N.; Pack, E. J., Jr.; ZuvelaJelaska, L.; Pelletier, J.; Panzenbeck, M.; Torcellini, C. A.; Proudfoot, J. R.; Nabozny, G. H.; Thomson, D. S. Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore. Bioorg. Med. Chem. Lett. 2014, 24, 1934–1940. 22. The osteocalcin assay measures the suppression of the production of osteocalcin upon stimulation with vitamin D in human MG-63 cells, an osteosarcoma cell line of osteoblast lineage. The maximum inhibition by the test compound is compared to prednisolone at 2 µM which is set to 100%. 23. Harcken, C. ; Riether, D.; Kuzmich, D.; Liu, P.; Betageri, R.; Ralph, M.; Emmanuel, M.; Reeves, J. T.; Berry, A.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-Jelaska, L.; Dinallo, R.; Bentzien, J.; Nabozny, G. H.; Thomson, D. S. Identification of highly efficacious glucocorticoid receptor agonists with a potential for reduced clinical bone side effects. J. Med. Chem. 2014, 57, 1583–1598. 24. Harcken, C.; Riether, D.; Liu, P.; Razavi, H.; Patel, U.; Lee, T.; Bosanac, T.; Ward, Y.; Ralph, M.; Chen, Z.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra-Khan, T. N.; Zuvela-Jelaska, L.; Patel, M.; Thomson, D. S.; Nabozny, G. S. Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate. ACS Med. Chem. Lett. 2014, 5, 1318–1323.

183 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Identification and Optimization of a Series of Non-Steroidal

Recommend Documents