p38α mitogen-activated protein kinase inhibitors: Optimization of a series of biphenylamides to give a molecule suitable for clinical progression

Journal of Medicinal Chemistry

Volumn 52, Issue 20, 2009, Pages 6257-6269

  Aston, Nicola M ^a   Bamborough, Paul ^a   Buckton, Jacqueline B ^a   Edwards, Christopher D ^a   Holmes, Duncan S ^a   Jones, Katherine L ^a   Patel, Vipulkumar K ^a   Smee, Penny A ^a   Somers, Donald O ^a   Vitulli, Giovanni ^a   Walker, Ann L ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5 [5 ((CYCLOPROPYLAMINO)CARBONYL) 2 METHYLPHENYL] N (CYCLOPROPYLMETHYL) 2 PYRIDINECARBOXAMIDE; 5 CHLORO N3 CYCLOPROPYL N4' (CYCLOPROPYLMETHYL) 6 METHYL 3,4' BIPHENYLDICARBOXAMIDE; 6 (5 CYCLOPROPYLCARBAMOYL 2 METHYL PHENYL) N CYCLOPROPYLMETHYL NICOTINAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N (1,2 DIMETHYLPROPYL) 3 PYRIDINECARBOXAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N (1,2,2 TRIMETHYLPROPYL) 3 PYRIDINECARBOXAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N (2 METHYLPROPYL) 3 PYRIDINECARBOXAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N (CYCLOPROPYLMETHYL) 3 PYRIDINECARBOXAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N [1,2 DIMETHYLPROPYL] 3 PYRIDINECARBOXAMIDE; 6 [5 ((CYCLOPROPYLAMINO)CARBONYL) 3 FLUORO 2 METHYLPHENYL] N [1,2,2 TRIMETHYLPROPYL] 3 PYRIDINECARBOXAMIDE; ANTIINFLAMMATORY AGENT; BIPHENYLAMIDE DERIVATIVE; INTERLEUKIN 1BETA; MITOGEN ACTIVATED PROTEIN KINASE 4 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; N 3 CYCLOPROPYL 5 FLUORO 6 METHYL N4' (TETRAHYDRO 2 FURANYLMETHYL) 3,4' BIPHENYLDICARBOXAMIDE; N 3 CYCLOPROPYL 5 FLUORO 6 METHYL N4' [(2 METHYL 1,3 THIAZOL 4 YL)METHYL] 3,4' BIPHENYLDICARBOXAMIDE; N 3 CYCLOPROPYL N 4' (CYCLOPROPYLMETHYL) 5 FLUORO 6 METHYL 3,4' BIPHENYLDICARBOXAMIDE; N 3 CYCLOPROPYL N4' (CYCLOPROPYLMETHYL) 4 FLUORO 6 METHYL 3,4' BIPHENYLDICARBOXAMIDE; N 3 CYCLOPROPYL N4' (CYCLOPROPYLMETHYL) 5,6 DIMETHYL 3,4' BIPHENYLDICARBOXAMIDE; N3 CYCLOPROPYL 5 FLUORO 6 METHYL N4' [2 (METHYLOXY)ETHYL] 3,4' BIPHENYLDICARBOXAMIDE; N3 CYCLOPROPYL 5 FLUORO N4' (2 HYDROXY 2 METHYLPROPYL) 6 METHYL 3,4' BIPHENYLDICARBOXAMIDE; PREDNISOLONE; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UNCLASSIFIED DRUG; AMIDE; BIPHENYL; BIPHENYL DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE 14; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFECT; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; NONHUMAN; RAT; RHEUMATOID ARTHRITIS; ANIMAL; ARTHRITIS; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG ANTAGONISM; DRUG DEVELOPMENT; HUMAN; MOUSE; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; ARTHRITIS, EXPERIMENTAL; BIPHENYL COMPOUNDS; DRUG DISCOVERY; HUMANS; MICE; MITOGEN-ACTIVATED PROTEIN KINASE 14; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN KINASE INHIBITORS; RATS;

EID: 70350077506     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9004779     Document Type: Article

References (27)

1. Taylor, P. C.; Williams, R. O.; Maini, R. N. Immunotherapy for rheumatoid arthritis. Curr. Opin. Immunol. 2001, 13 (5), 611-616.
2. Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S. W.; Strickler, J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J. L.; Young, P. R. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994, 372, 739-746.
3. Herlaar, E.; Brown, Z. p38 MAPK signalling cascades in inflammatory disease. Mol. Med. Today 1999, 5, 439-447.
4. Peifer, C.; Wagner, G.; Laufer, S. New approaches to the treatment of inflammatory disorders small molecules inhibitors of p38 MAP kinase (Review). Curr. Top. Med. Chem. 2006, 6, 113-149.
5. Goldstein, D. M.; Gabriel, T. Pathway to the clinic: Inhibition of p38 MAP kinase. A review of ten chemotypes selected for development (Review). Curr. Top. Med. Chem. 2005, 5, 1017-1029.
6. McClure, K. F.; Letavic, M. A.; Kalgutkar, A. S.; Gabel, C. A.; Audoly, L.; Barberia, J. T.; Braganza, J. F.; Carter, D.; Carty, T. J.; Cortina, S. R.; Dombroski, M. A.; Donahue, K.M.; Elliott, N. C.; Gibbons, C. P.; Jordan, C. K.; Kuperman, A. V.; Labasi, J. M.; LaLiberte, R. E.; McCoy, J. M.; Naiman, B. M.; Nelson, K. L.; Nguyen,H.T.; Peese, K.M.; Sweeny, F. J.;Taylor, T. J.;Trebino,C. E.;Abramov,Y.A.; Laird, E. R.;Volberg,W.A.; Zhou, J.; Bach, J.; Lombardo, F. Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development. Bioorg.Med. Chem. Lett. 2006, 16 (16), 4339-4344.
7. Natarajan, S. R.; Wisnoski, D. D.; Thompson, J. E.; O'Neill, E. A.; O'Keefe, S. J. p38 MAP kinase inhibitors. Part 3: SAR on 3,4-dihydropyrimido[4, 5-d]pyrimidones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones. Bioorg. Med. Chem. Lett. 2006, 16 (16), 4400-4404.
8. Dominguez, C.; Powers, D. A.; Tamayo, N. p38 MAP kinase inhibitors: Many are made, but few are chosen. Curr. Opin. Drug Dis. Dev. 2005, 8 (4), 421-430.
9. Lee, M. R.; Dominguez, C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38α protein. Curr. Med. Chem. 2005, 12, 2979-2994.
10. Angell, R. M.; Bamborough, P.; Cleasby, A.; Cockerill, S. G.; Jones, K. L.; Mooney, C. J.; Somers, D. O.; Walker, A. L. Biphenyl amide p38 kinase inhibitors: discovery and binding mode. Bioorg. Med. Chem. Lett. 2008, 18 (1), 318-323.
11. Angell, R. M.; Angell, T. D.; Bamborough, P.; Brown, D.; Brown, M.; Buckton, J. B.; Cockerill, S. G.; Edwards, C. D.; Jones, K. L.; Longstaff, T.; Smee, P. A.; Smith, K. J.; Somers, D. O.; Walker, A. L.; Willson, M. Biphenyl amide p38 kinase inhibitors. 2: Optimization and SAR. Bioorg. Med. Chem. Lett. 2008, 18 (1), 324-328.
12. Angell, R. M.; Aston, N. M.; Bamborough, P.; Buckton, J. B.; Cockerill, S. G.; de Boeck, S. J.; Edwards, C. D.; Holmes, D. S.; Jones, K. L.; Laine, D. I.; Patel, S.; Smee, P. A.; Smith, K. J.; Somers, D. O.; Walker, A. L. Biphenyl amide p38 kinase inhibitors. 3: Improvement of cellular and in vivo activity. Bioorg. Med. Chem. Lett. 2008, 18 (15), 4428-4432.
13. Angell, R. M.; Angell, T. D.; Bamborough, P.; Bamford, M. J.; Chung, C.; Cockerill, S. G.; Flack, S. S.; Jones, K. L.; Laine, D. I.; Longstaff, T.; Ludbrook, S.; Pearson, R.; Smith, K. J.; Smee, P. A.; Somers, D. O.; Walker, A. L. Biphenyl amide 38 kinase inhibitors. 4: DFG-in and DFG-out binding modes. Bioorg. Med. Chem. Lett. 2008, 18 (15), 4433-4437.
14. Schrier, D. C.; Schimmer, R. C.; Flory, C. M.; Tung, D.K-L.; Ward, P. A. Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. J. Leukocyte Biol. 1998, 63, 359-363. (Pubitemid 28106850)
15. Courtenay, J. S.; Dallman, M. J.; Dayan, A. B.; Martin, A.; Mosedale, B. Immunisation against heterologous type II collagen-induced arthritis in mice. Nature 1980, 2843, 666-668.
16. Joosten, L. A. B.; Helsen, M. M. A.; van de Loo, F. A. J.; van den Berg, W. B. Anticytokine treatment of established collagen-induced arthritis in DBA/1 mice. Arthritis Rheum. 1996, 39, 797-809.
17. Joosten, L. A. B.; Helsen, M. M. A.; Saxne, T.; van de Loo, F. A. J.; Heinegard, D.; van den Berg, W. B. IL-1αβ blockade prevents cartilage and bone destruction in murine type II collagen induced arthritis whereas TNF-α blockade only ameliorates joint inflammation. J. Immunol. 1999, 163, 5049-5055.
18. Williams, R. O.; Feldmann, M.; Maini, R. N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9784-9788.
19. Valko, K.; Bevan, C.; Reynolds, D. Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to Log P/log D. Anal. Chem. 1997, 69 (11), 2022-2029.
20. HSA binding constants were obtained by high performance affinity chromatography on a column of immobilized human serum albumin.
21. Solubilities were measured either from dissolution of solid into water buffered to pH7.4 or by precipitation from 10 mM DMSO solution.
22. Edwards C. D. Drug Metabolism Discussion Group, Sept 2004. Poster included in Supporting Information.
23. Okada, S.; Kayakiri, N.; Sawaday, Y.; Tanaka, H.; Hashimoto, M. Indole derivatives. World Patent WO93/03012, 1993.
24. Schlosser, M.; Geneste, H. The super base approach to flurbiprofen: an exercise in optionally site-selective metalation. Chem.;Eur. J. 1998, 4 (10), 1969-1973. (Pubitemid 28485849)
25. Otwinowski. Z.; Minor, W. Processing of X-ray Diffraction Data Collected in Oscillation Mode. Macromolecular Crystallography, Part A; Methods in Enzymology, Vol.276; Carter, C.W., Jr., Sweet, R. M., Eds.; Academic Press: New York, 1997; pp 307-326.
26. Collaborative Computational Project Number 4. The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50 (5), 760-763.
27. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of Macromolecular Structures by the Maximum-Likelihood Method. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, 53 (5), 240-255.