Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 20, 2009, Pages 5851-5856

  Selness, Shaun R ^a   Devraj, Rajesh V ^a   Monahan, Joseph B ^a   Boehm, Terri L ^a   Walker, John K ^a   Devadas, Balekudru ^a   Durley, Richard C ^a   Kurumbail, Ravi ^a   Shieh, Huey ^a   Xing, Li ^a   Hepperle, Michael ^a   Rucker, Paul V ^a   Jerome, Kevin D ^a   Benson, Alan G ^a   Marrufo, Laura D ^a   Madsen, Heather M ^a   Hitchcock, Jeff ^a   Owen, Tom J ^a   Christie, Lance ^a   Promo, Michele A ^a   Hickory, Brian S ^a   Alvira, Edgardo ^a   Naing, Win ^a   Blevis Bal, Radhika ^a   more..

^a PFIZER INC   (United States)

Author keywords

p38 kinase; Pyridinones

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 5 (2,6 DICHLOROPHENYL) 2 (2,4 DIFLUOROPHENYLTHIO)PYRIMIDO[1,6 B]PYRIDAZIN 6 ONE; ANTIINFLAMMATORY AGENT; BENZYLOXY PYRIDINONE; HYDROXY PYRIDINONE; MITOGEN ACTIVATED PROTEIN KINASE P38; PYRIDONE DERIVATIVE; SC 25028; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHRONIC INFLAMMATION; CONTROLLED STUDY; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG STRUCTURE; FEMALE; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IN VIVO STUDY; MALE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-INFLAMMATORY AGENTS; BINDING SITES; CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; HUMANS; JNK MITOGEN-ACTIVATED PROTEIN KINASES; MALE; MICROSOMES, LIVER; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; PYRIDONES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 70349194480     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.082     Document Type: Article

References (20)

1. Arend W.P., and Dayer J.M. Arthritis Rheum. 33 (1990) 305
2. Firestein G.S., Alvaro-Gracia J.M., and Maki R. J. Immunol. 144 (1990) 3347
3. Rutgeerts P., D'Haens G., Targan S., Vasiliauskas E., Hanauer S.B., Present D.H., Mayer L., Van Hogezand R.A., Braakman T., DeWoody K.L., Shaible T.F., and Van Deventer S.J.H. Gastroenterology 117 (1999) 761
4. Ulfgren A.K., Andersson U., Engstrom M., Klareskog L., Maini R.N., and Taylor P.C. Arthritis Rheum. 43 (2000) 2391
5. Foster M.L., Halley F., and Souness J.E. Drug News Perspect. 13 (2000) 488
6. Lee J.C., Laydon J.T., McDonnell P.C., Gallagher T.F., Kumar S., Green D., MeNulty 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., and Young P.R. Nature 372 (1994) 739
7. Cohen P. Trends Cell Biol. 7 (1997) 353
8. Widmann C., Gibson S., Jarpe M.B., and Johnson G.L. Physiol. Rev. 79 (1999) 143
9. Ono K., and Han J. Cell Signal. 12 (2000) 1
10. Johnson G.L., and Lapadat R. Science 298 (2002) 1911
11. Jackson P.F., and Bullington J.L. Curr. Top. Med. Chem. 2 (2002) 1011
12. Natarajan S.R., and Doherty J.B. Curr. Top. Med. Chem. 5 (2005) 987
13. Bemis, G. W.; Salituro F. G.; Duffy, J. P.; Cochran, J. E.; Harrington, E. M.; Murcko, M. A.; Wilson, K. P.; Su, M.; Galullo, V. P. US Patent 7365,072 B2, 2008.
14. Adams J.L., Boehm J.C., Kassis S., Gorycki P.D., Webb E.F., Hall R., Sorenson M., Lee J.C., Ayrton A., Griswold D.E., and Gallagher T.A. Biorg. Med. Chem. Lett. 8 (1998) 3111
15. The atomic coordinates for the X-ray structure of p38a in complex with 1 have been deposited in the RCSB: rcsb id code-a RCSB053406; PDB code-3HP2.
16. The atomic coordinates for the X-ray structure of p38a in complex with 2 have been deposited in the RCSB: rcsb id code-RCSB053409; PDB code-3HP5.
17. Castillo S., Ouadahi H., and Herault V. Bull. Soc. Chim. Fr. 7-8 (1982) 257
18. Compounds were pre-dosed in male Lewis rats at various time points prior to an iv challenge with lipopolysaccharide. Blood was drawn 1.5 h post-challenge and TNF-α levels were evaluated by ELISA.
19. The Pfizer Institutional Animal Care and Use Committee reviewed and approved the animal use in these studies. The animal care and use program is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.
20. Metabolic stability was assessed in vitro by incubating 2 μM test compound with human or rat liver microsomes, NADPH and buffer at 37 °C for 45 min and measuring percent compound remaining by a precipitation procedure followed by LC/MS analysis.