Discovery and Optimization of 4-(8-(3 ... - ACS Publications

Subscriber access provided by UNSW Library

Drug Annotation

The Discovery And Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6yl)transcyclohexanecarboxylic acid, An Improved PDE4 Inhibitor For The Treatment of Chronic Obstructive Pulmonary Disease (COPD) Neil John Press, Roger J Taylor, Joseph D Fullerton, Pamela Tranter, Clive McCarthy, Thomas H Keller, Nicola Arnold, David Beer, Lyndon Brown, Robert Cheung, Julie Christie, Alastair Denholm, Sandra Haberthuer, Julia D. I. Hatto, Mark Keenan, Mark K Mercer, Helen Oakman, Helene Sahri, Andrew R Tuffnell, Morris Tweed, and Alexandre Trifilieff J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Aug 2015 Downloaded from http://pubs.acs.org on August 20, 2015

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 22

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 Discovery And Optimization of 4-(8-(3Fluorophenyl)-1,7-naphthyridin-6yl)transcyclohexanecarboxylic acid, An Improved PDE4 Inhibitor For The Treatment of Chronic Obstructive Pulmonary Disease (COPD). Neil J. Press*a, Roger J. Taylora, Joseph D. Fullertona, Pamela Trantera, Clive McCarthya, Thomas H. Kellera, Nicola Arnolda, David Beera, Lyndon Browna, Robert Cheunga, Julie Christiea, Alastair Denholma, Sandra Haberthuera, Julia D. I. Hattoa, Mark Keenana, Mark K. Mercera, Helen Oakmana, Helene Sahria, Andrew R. Tuffnella, Morris Tweeda and Alexandre Trifilieffa a

Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK

KEYWORDS: PDE4, phosphodiesterase, therapeutic index, solubility-based optimisation

ACS Paragon Plus Environment

1


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 22

ABSTRACT

Herein we describe the optimisation of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin6-yl)transcyclohexanecarboxylic acid. Although Compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprised of multiple escalating doses, and the resultant achievement of high plasma drug levels without associated nausea or emesis.

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is currently the fourth most common cause of death in the world according to the World Health Organization (WHO)1. The pulmonary component of COPD is characterized by progressive airflow limitation that is not fully reversible, resulting from mucosal inflammation and oedema, bronchoconstriction, increased secretions in the airways and loss of elastic recoil2, 3. Inhaled corticosteroids and bronchodilator agents are the main therapies used for the treatment of COPD4 and have modest beneficial effects on health-related quality of life and FEV15. Steroids are, however, relatively ineffective at suppressing the airway wall thickening and luminal occlusion in COPD patients6 and the consequent disease progression. There is thus a high unmet medical need for novel effective therapies to treat COPD. The phosphodiesterase (PDE) family (represented by four genes: PDE4A, B, C and D) are the primary cAMP-specific hydrolase enzymes and are key modulators in the spacial and temporal


2

Page 3 of 22

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


regulation of intracellular cAMP signalling. PDE4 inhibitors have attracted considerable interest as potential therapeutic agents for CNS diseases and pathologies with a strong inflammatory component including chronic obstructive pulmonary disease. Indeed, ibudilast7, theophylline8 and roflumilast9 are utilized clinically, albeit only the latter has high PDE4 selectivity. Unfortunately, however, many PDE4 inhibitors have failed in early development due to low therapeutic ratios – the most commonly reported clinical adverse event in humans being nausea and emesis. Despite efforts to provide a drug with minimal side effects, it is clear that this class of enzyme inhibitor produces compounds with a very narrow therapeutic index (roflumilast is dosed at 0.5mg q.d.)10. For this reason, and in the absence of strong evidence to support a particular selectivity-based hypothesis to mitigate adverse events, we designated a key aim of our research program in this field to provide a drug compound which would have exemplary physico-chemical properties, allowing us to model and predict human pharmacokinetics with a high degree of confidence, and to modify exposure to the drug by fine tuning dosing. A key part of this strategy clearly would be to produce a highly soluble compound, since low solubility leads to variability in ADME properties across a cohort, such as slow absorption and unpredictable exposure11. Indeed, this is the kind of variable profile that we had observed in the rat with prototype compoud 1 (NVP-ABE171), which was a very potent PDE4 inhibitor, with good oral efficacy in rat models of inflammation but with very poor solubility and variable pharmacokinetics (PK) (figure 1)12-14.


3


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 22

O OH

N

Inhibition of PDE4 PDE4A IC50=602nM PDE4B IC50=34nM PDE4D IC50=1.5nM

N Solubility pH6.8 = 2.3mg/L N N O

Pharmacokinetics F (rat) = 8+/- 3%

NVP-ABE171

Figure 1. Structure and properties of 1

As recently described15, we were able to take this compound as the starting point for our campaign to produce a clinical candidate with exemplary pharmacokinetic properties, which we were able to find in compound (2). As will be described, we found that reproducible, predictable pharmacokinetics in man was critical to achieving high plasma levels without accompanying nausea/emesis. This was achieved through a novel dosing regime comprised of multiple escalating doses (whereas a single dose to high plasma level did result in emesis).

Figure 2. Structure and properties of 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6yl)transcyclohexanecarboxylic acid (2)


4

Page 5 of 22

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


Thus, by primarily solubility-based design modification of a potent but sub-optimal PDE4 inhibitor, we were able to produce a refined molecule with retained efficacy in animal models of inflammation, but with examplary suitability to dosing in man.

DISCUSSION Various creative solutions have been put forward as to how to reduce or mitigate the side effect profile of nausea/emesis associated with PDE4 inhibitors. These include engineering selectivity against the rolipram binding site of PDE416, targeting a specific PDE4 subtype17-19, designing allosteric modulators (partial inhibitors)20, delivering the drug topically21-23 and co-dosing with a synergistic partner24. At the start of our program in this area, we felt that it was unclear which, if any, of these approaches had a reasonable likelihood of delivering a successful molecule. Given that, based on the history of the area, therapeutic index was likely to be a significant issue, we made it a key aim of our program to deliver a molecule in which we had confidence that the exposure would be controlled precisely and accurately through dosing, thus giving us the best possible chance to find the ‘sweet spot’ of exposure vs response. In hand we had compound 1 (fig.1), which was a highly potent PDE4 inhibitor, and even efficacious in vivo, despite a very poor and irreproducible PK profile. We reasoned that improving solubility would be critical to achieving our aims, and could immediately visualise several design strategies to enable this. The core 1,7-naphthyridine scaffold could be kept but we would break up what we saw as the very flat, highly aromatic structure of 1 - we felt that the presence of 5 aromatic rings was likely leading to a well-packed crystal structure with slow dissolution rate. We hypothesized that removal of two aromatic rings was feasible: the


5


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 22

oxadiazole ring (replacing it with meta-electron withdrawing groups) and the benzoic acid moiety (replacing it, for example, with a saturated group). These changes were proposed in order to introduce a more three-dimensional morphology to the compound, the aim being overall to weaken the crystal structure of 1, lower the melting point and improve dissolution rate. We were keen to maintain the presence of the carboxylic acid in the molecule both as a handle for salt formation, and also with an aim to limiting the penetration of the compound into the central nervous system, it being considered that this may help to reduce the nausea/emesis side effect profile25 - Fig. 3. However, the brain penetration of the compounds synthesised was not specifically measured and this was not a major consideration given that the emetic center in the area postrema is outside the blood-brain-barrier. CO2H

CO2H Linker

N

N/C

N N

N

N N O

Electron withdrawing group

(1)

Figure 3. Design strategy for producing more soluble PDE4 inhibitors Our initial progress was greatly facilitated by the availability of 200g of a key intermediate – naphthyridine 3 with two functional handles for derivitisation (Fig.4).


6

Page 7 of 22

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


6

R2 N R1

N

N Direct SNAr reaction OTf

OTf N

N

R

(4)

Suzuki reaction N

N R3

Br 6

(3) R

( )

n

Negishi coupling

N

N

(5)

R

Figure 4. Rapid functionalisation strategy from intermediate 3. Through this synthetic methodology (previously described in further detail15) we were able to rapidly produce a large array of novel PDE4 inhibitors with varying physicochemical parameters. The spread and general physicochemical space of the new array is demonstrated in figure 5. Here it can be seen that almost universally, all modifications reduced both cLogP and PSA compared to starting point 1. The effect of these changes on solubility as measured in a high throughput kinetic solubility assay is less clear – the solubilities relative to 1 showed no clear trend for improvement with any measured or calculated parameter, nor with linker atom at the 6position (nitrogen or carbon). As table 1 shows with selected data points, there is no clear relationship between kinetic (high throughput) solubility and thermodynamic solubility. While kinetic solubility26 is advantageous for the measurement of large compound numbers, it does have the disadvantage that compound samples are pre-solubilised in DMSO prior to dispensing in the test media, and therefore there is no readout reflecting a measure of the rate of dissolution. Arguably the effects that we were looking to modify in our structural changes relate to the


7


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 8 of 22

strength of the crystal lattice formed from each molecule, and therefore solubility effects would be more apparent in a thermodynamic solubility assay, in which solubility is measured from the solid – although degree of crystallinity is not taken into account at this stage.

Figure 5. Scatter plot showing the spread of cLogP and PSA of new PDE4 inhibitors synthesised. Data points are shaped according to high throughput kinetic solubility relative to 1


8

Page 9 of 22

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


(, solubility increased; , solubility decreased; —, equivalent solubility), coloured by series (blue=6-amino, brown=6-carbon, red=1) and sized by pIC50 at PDE4D (larger=more potent; pIC50 range= 4

19 ±6

4b R = F

>0.07

>4

51 ±12

5a R = CN

0.02

0.43

41 ±20

5b R = Cl

0.1

0.14

30 ±23

2R=F

0.01

0.92

32 ±10

5c R = OMe

0.02

0.15

64 ±22

Compounds

CO2H N N

hPDE4D IC50 SEM (nM)

±

N

R

CO2H

N

N

R a

Kinetic solubility is measured by Nephelometric titration in 96-well microtiterplates at 250C

in 0.067M phosphate buffer, pH6.8 (chloride free). bThermodynamic solubility determined using the dissolution template potentiometric titration method with a p-SOL3 solubility analyser under Argon at 250C in solutions containing 0.15M KCl27.


9


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 22

The focus on optimising against these physicochemical parameters allowed us into the chemical space defined by the “Egan Egg”28, in which compounds with a certain balance of cLogP and PSA, defined by an ellipse (Figure 6), have been shown historically to have a higher likelihood of good oral bioavailability. Indeed, as shown in Table 2, a representative selection of these new compounds showed much improved oral biovailabilty compared to 1.

Figure 6. Scatter plot showing distribution of new PDE4 inhibitors against PSA and cLogP. Points are coloured by series (blue=6-amino, brown=6-carbon, red=1). Optimal property space is described by the “Egan Egg” – compounds within the green ellipse are shown historically to have good oral bioavailability, those between the red and green ellipses are historically ‘borderline’ or variable for oral bioavailability, while compounds outside the red ellipse typically have poor oral bioavailability.28


10

Page 11 of 22

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


Table 2. Pharmacokinetic parameters of PDE4 inhibitors in the rata BAV (%)

i.v.

i.v.

p.o.

p.o.

p.o.

p.o.

Vss (L/Kg)

Cl (mL/min / kg)

Cmax (uM)

Tmax (min)

AUC (uM/min)

T1/2 (min)

1

0.37 ±0.003

2.34 ±0.39

2.4 ±1.4

210 ±87

523 ±140

12 ±7

8 ±3

5ab

0.25 ±0.06

0.22 ±0.1

8.3 ±1.4

1500 ±990

112900 ±42700

11600 ±270

92.1 ±17.8

0.09 (n=2)

0.64 (n=2)

4.6 ±1.0

4408 ±799

522 ±31

0.72 (n=2)

1.16 (n=2)

2.8 ±0.6

0.24 (n=2)

2.07 (n=2)

4.82 ±0.97

2c

4ad

4be

(25h) 200 ±52

(8 days)

(8.7h) 129 ±37

2768 ±566

1362 ±290 (23h)

173 ±104

3919 ±1655

999 ±362 (16h)

51.5 ±9.3 157.5 ±32.2 69.6 ±12.0

a

Error limits are shown as ± SEM where n ≥ 3 Compound dosed as the potassium salt. Vehicle (i.v. and p.o.): PBS to 4.2µM/mL dosed at 4.2µM/kg c Compound dosed as the potassium salt. Vehicle (i.v. and p.o.): PBS to 2.1µM/mL dosed at 2.1µM/kg d Vehicle (i.v.): 25/75 PEG200/PBS to 1.05µM/mL dosed at 1.05µM/kg; (p.o.): 25/75 PEG200/PBS to 2.1µM/mL dosed at 2.1µM/kg e Compound dosed as the sodium salt. Vehicle (i.v.) 25/75 PEG200/PBS to 2.1µM/mL dosed at 2.1µM/kg; (p.o.): 25/75 PEG200/PBS to 4.2µM/mL dosed at 4.2µM/kg b

While all the compounds in Table 2 have excellent bioavailability and generally favourable pharmacokinetic parameters, it is worth remarking on the exceptionally long half life of compound 5a. After a single oral dose of 1.6mg/kg in the rat, this compound was still showing plasma concentrations of 6-8µM after 3 days! Investigations into the reasons behind this extremely long half life did not come to a convincing conclusion – for example a bile duct


11


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 22

cannulation experiment, designed to detect enterohepatic recirculation, did not have any effect on the pharmacokinetic parameters up to 6h. We reasoned that a combination of low intrinsic clearance, as measured in rat liver microsomes, and high plasma protein binding were the main contributory factors towards this very long half life. Fortunately, we were able to further modulate in vivo clearance rates, without compromising affinity to PDE4, through judicious choice of substitution at the 6-position, as summarised in Table 3. Thus introducing a heteroatom into the cyclohexane ring increases in vivo clearance considerably, without impacting other key parameters significantly (compare 4a with 5a). Removal of the carboxylic acid moiety further increased clearance, with the fastest rate in this set being observed with the primary alcohol 7. Table 3. Pharmacokinetic parameters of PDE4 inhibitors in the rata

i.v.

i.v.

i.v.

hPDE4D

R Vss (L/Kg) Cl (mL/min/ kg) T1/2 (min) IC50 (nM) O

4a

0.7

1.2

645

19

0.2

0.2

5180

41

OH N

5a

O OH


12

Page 13 of 22

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


O

6

2.9

72

36

8

1.7

89

15

13

1.5

36

32

22

5.1

66

96

3

NH2 N

7

OH N OH

8 N

9

O N a

i.v. data shown, vehicle: PBS or 25/75 PEG200/PBS

Thus, we had in hand multiple compounds which could be further differentiated based on in vivo animal models of efficacy and toxicology, as well as in vitro human assay systems. This data and methodology has been previously described, leading to the identification of compound 2 as the final clinical candidate.15 One of the key aims of this project had been to design a drug with exemplary solubility and pharmacokinetic properties. Since the on-target side effects of PDE4 inhibitors in man were well known and anticipated, it was felt that highly predictable and reproducible pharmacokinetics would be greatly beneficial in maintaining a high therapeutic index. Gratifyingly we found that 2 was well absorbed in healthy volunteers and patients, with AUC and Cmax dose proportional in the range of 0.5-25mg single oral doses given once daily (q.d.) in the fed state. The data derived from the single dose pharmacokinetic assessments was used to create a model to select the doses in a dosing regimen designed to produce a gradual increase in exposure, with the aim of inducing


13


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 22

tolerance and a better tolerability profile. The plasma levels attained were very closely in line with what had been predicted in silico (Fig.7).

Figure 7. Graph showing plasma concentration of 2 in COPD patients after oral dosing q.d.. Red line: predicted plasma concentration; Black circles: measured plasma concentrations from n=12 patients with mild/moderate COPD. In Fig.7, showing the titrated repeat dosing study, can be seen the specific dose regimen used, which enabled the slow increase of plasma levels of the drug over a period of 14 days. It was found that by this method the side effects of nausea and vomiting were able to be successfully obviated, giving an improved tolerability profile in the multiple dose part of the study compared to the single dose parts of the study. This data is summarised in Fig.8, which shows the percent of subjects with nausea and/or vomiting versus the plasma concentration of the drug. It can be


14

Page 15 of 22

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


seen that high plasma concentrations achieved through delivery of a single dose led to nausea/vomiting, whereas the same plasma concentrations achieved through a regime of multiple escalating doses gave significantly reduced nausea/side effects.

Figure 8. Graph relating percentage of human subjects with nausea and/or vomiting to plasma concentration of 2. Plasma concentrations were achieved either through a single (0.5mg-25mg) q.d. oral dose (

, healthy subjects, n=6) or multiple escalating q.d. oral doses ( , COPD

patients, n=12) of 2.

CONCLUSIONS We have shown that through rational design we have been able to improve the solubility and pharmacokinetic profiles of a series of PDE4 inhibitors, compared to the parent compound. The


15


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 22

production of a range of compounds with subtle differences in structure and pharmaceutical properties led to the selection of the compound with the best overall profile – 2. It was shown that this compound did indeed exhibit highly predictable pharmacokinetics in human subjects, which enabled a novel escalating dosing regime in which high plasma levels of the drug could be achieved in the absence of significant nausea or emesis. The precise mechanism of the tolerance induced through gradually increasing exposure is not understood, but it is interesting to consider alternative delivery modalities which may achieve simlar results; for example, a slow release formulation, prodrug or active metabolite. Indeed, historically successful PDE4 inhibitors may incorporate some element of this - for example Roflumilast may be metabolised in vivo to the highly active N-oxide metabolite. Further results against an efficacy biomarker will be reported in due course. AUTHOR INFORMATION Corresponding Author Dr Neil J. Press, [email protected], +41 61 324 1111 Present Addresses Novartis Institutes For Biomedical Research, Fabrikstrasse 22, Basel CH4056, Switzerland Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ABBREVIATIONS FEV1, forced expiratory volume in 1 second;


16

Page 17 of 22

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


REFERENCES (1) Murray, C. J.; Lopez, A. D. Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet 1997, 349, 1498-1504. (2) Pauwels, R. A.; Buist, A. S.; Ma, P.; Jenkins, C. R.; Hurd, S. S. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung and Blood Institute and World Health Organization global initiative for chronic obstructive lung disease (GOLD): executive summary. Respir Care 2001, 46, 798-825. (3) Rabe, K. F. Guidelines for chronic obstructive pulmonary disease treatment and issues of implementation. Proc. Am. Thorac. Soc. 2006, 3, 641-644. (4) Gosens, R.; Zaagsma, J.; Meurs, H.; Halayko, A. J. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res 2006, 7, 73. (5) Mahler D. A.; Wire, P.; Horstman, D.; Chang, C. N.; Yates, J.; Fischer, T.; Shah, T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2002, 166, 1084-1091 (6) Hogg, J. C.; Chu, F. S.; Tan W. C.; Sin D. D.; Patel, S. A.; Pare, P. D.; Martinez, F.J.; Rogers, R.M.; Make, B.J.; Criner, G.J.; Cherniak, R.M.; Sharafkhaneh, A; Luketich, J.D.; Coxson, H.O.; Elliott, W.M.; Sciurba, F.C. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am. J. Respir. Crit. Care Med. 2007, 176, 454-459


17


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 22

(7) Kishi, Y.; Ohta S.; Kasuya N.; Tatsumi, M.; Sawada, M.; Sakita, S.; Ashikaga, T.; Numano, F. Ibudilast modulates platelet-endothelium interaction mainly through cyclic GMPdependent mechanism. J. Card. Pharm. 2000, 36[1], 65-70. (8) Akram, M. F.; Nasiruddin, M.; Ahmad, Z.; Rahat, A. Doxofylline and theophylline: a comparative clinical study. J. Clin. and Diag. Res. 2012, 6[10], 1681-1684 (9) Lipari, M.; Benipal, H.; Kale-Pradhan, P. Roflumilast in the management of chronic obstructive pulmonary disease. Am. J. Health Sys. Pharm. 2013, 70[23], 2087-2095. (10) Fabbri, L. M.; Beghe, B.; Yasothan, U.; Kirkpatrick, P. Roflumilast. Nat. Rev. Drug Disc. 2010, 9[10], 761-762. (11) Neervannan S. Strategies to impact solubility and dissolution rate during drug lead optimization: salt selection and prodrug design approaches. Am. Pharm. Rev. 2004, 7[5], 110113. (12) Hersperger, R.; Dawson, J.; Mueller, T. Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl[1,7]naphthyridine-6-yl)-benzoic acid: a potent and selective phosphodiesterase type 4D inhibitor. Bioorg. and Med. Chem. Lett. 2002, 12, 233-235. (13) Trifilieff, A.; Wyss, D.; Walker, C.; Mazzoni, L.; Hersperger, R. Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6yl)benzoic acid (4), a 1,7-naphthyridine derivative, with anti-inflammatory activities. J. Pharmacol. Exp. Ther. 2002, 301, 241-248.


18

Page 19 of 22

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


(14) Tigani, B.; Cannet C.; Zurbruegg, S.; Schaeublin, E.; Mazzoni, L.; Fozard, J. R.; Beckmann, N. Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging. Br. J. Pharmacol. 2003, 140, 239-246. (15) Press, N. J.; Taylor, R. J.; Fullerton, J.D.; Tranter, P.; McCarthy, C.; Keller, T.H.; Arnold, N.; Beer, D.; Brown, L.; Cheung, R.; Christie, J.; Denholm, A.; Haberthuer, S.; Hatto, J.D.I.; Keenan, M.; Mercer, M.K.; Oakman, H.; Sahri, H.; Tuffnell, A.; Tweed, M.; Tyler, J.W.; Wagner, T.; Fozard, J.R.; Trifilieff, A. Solubility-driven optimization of phosphodiesterase-4 inhibitors leading to a clinical candidate. J. Med. Chem. 2012, 55[17], 7472-7479. (16) Souness, J. E.; Rao, S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal. 1997, 9, 227. (17) Robichaud, A.; Stramatiou, P. B.; Jin, S. L.; Lachance, N.; MacDonald, D.; Laliberte, F; Liu, S.; Huang, Z.; Conti, M.; Chan, C-C. Deletion of phosphodiesterase 4D in mice shortens a2adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J. Clin. Invest. 2002, 110, 1045-1052. (18) Fox, D.; Burgin, A. B.; Gurney, M. E. Structural basis for the design of selective phosphodiesterase 4B inhibitors. Cellular Signalling 2014, 26[3], 657-663. (19) Goto, T.; Shiina, A.; Murata, T.; Tomii, M.; Yamazaki, T.; Yoshida, K-i.; Yoshino, T.; Suzuki, O.; Sogawa, Y.; Mizukami, K.; Takagi, N.; Yoshitomi, T.; Etori, M.; Tsuchida, H.; Mikkaichi, T.; Nakao, N.; Takahashi, M.; Takahashi, H.; Sasaki, S. Identification of the 5,5dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors. Bioorg. and Med. Chem. Lett. 2014, 24[3], 893-899.


19


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 20 of 22

(20) Burgin, A. B.; Magnusson, O. T.; Singh, J.; Witte, P.; Staker, B.L.; Bjornsson, J.M.; Thorsteinsdottir, M.; Hrafnsdottir, S.; Hagen, T.; Kiselyov, A.S.; Stewart, L.J.; Gurney, M. E. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat. Biotech. 2010, 28[1], 63-70. (21) Baumer, W.; Hoppmann, J.; Runfeldt, C.; Kietzmann, M. Inflamm. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflammation & Allergy Drug Targets 2007, 6(1), 17-26. (22) Watz, H.; Mistry, S. J.; Lazaar, A. L. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm. Pharm. & Ther. 2013, 26[5], 588-595. (23) Vestbo, J.; Tan, L.; Atkinson, G.; Ward, J. A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur. Resp. J. 2009, 33[5], 10391044. (24) Press, N. J.; Banner, K. H. PDE4 Inhibitors: A review of the current field. Prog. Med. Chem. 2009, 47, 37-74. (25) Aoki, M.; Funkunaga, M.; Sugimoto, T.; Hirano, Y.; Kobayashi, M.; Honda, K.; Yamada, T. Studies on mechanisms of low emetogenicity of YM976, a novel phosphodiesterase type 4 inhibitor. J. Pharmacol. Exp. Ther. 2001, 298[3], 1142-1149. (26) Lipinski, C. A.; Lombardo, L.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.


20

Page 21 of 22

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


(27) Faller, B High throughput physicochemical profiling: potential and limitations. In Analysis and purification methods in combinatorial chemistry; Yan, B., Ed; John Wiley & Sons, Inc.: Hoboken, N.J., 2004; pp 369-406. (28) Egan, W. J.; Merz Jr, K. M.; Baldwin, J. J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43[21], 3867-3877.


21


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 22

TABLE OF CONTENTS GRAPHIC


22

Discovery and Optimization of 4-(8-(3 ... - ACS Publications

Recommend Documents