Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 2, 2010, Pages 469-473

  Jerome, Kevin D ^a   Rucker, Paul V ^a   Xing, Li ^a   Shieh, Huey S ^a   Baldus, John E ^a   Selness, Shaun R ^a   Letavic, Michael A ^a   Braganza, John F ^a   McClure, Kim F ^a  

^a PFIZER INC   (United States)

Author keywords

Kinase; p38; Triazolopyridines

Indexed keywords

CARBENE; ETHYLENE; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; MOLECULAR SCAFFOLD; PYRIDINE DERIVATIVE; SULFUR; TRIAZOLOPYRIDINE; UNCLASSIFIED DRUG;

ARTICLE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME BINDING; MOLECULAR MODEL; STRUCTURE ACTIVITY RELATION; X RAY;

ANIMALS; BENZAMIDES; BICYCLO COMPOUNDS, HETEROCYCLIC; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; MICROSOMES, LIVER; MODELS, CHEMICAL; MODELS, MOLECULAR; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 72249115112     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.11.114     Document Type: Article

References (25)

1. Dominguez C., Tamayo N., and Zhang D. Exp. Opin. Ther. Pat. 15 (2005) 801
2. Foster M.L., Halley F., and Souness J.E. Drug News Perspect. 13 (2000) 488
3. 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
4. Arend W.P., and Dayer J.M. Arthritis Rheum. 33 (1990) 305
5. Firestein G.S., Alvaro-Gracia J.M., and Maki R. J. Immunol. 144 (1990) 3347
6. 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
7. Ulfgren A.K., Andersson U., Engstrom M., Klareskog L., Maini R.N., and Taylor P.C. Arthritis Rheum. 43 (2000) 2391
8. Enbrel is a marketed soluble TNF-α receptor and Remicade is marketed as a TNF-a antibody therapy:. Jarvis B., and Faulds D. Drugs 57 (1999) 945
9. Seymour H.E., Worsley A., Smith J.M., and Thomas S.H.L. Br. J. Clin. Pharmacol. 51 (2001) 201
10. Rutgeerts P.J. Aliment. Pharmacol. Ther. 13 (1999) 9
11. For other clinical examples of p-38 map kinase inhibitors efficacy see:. Ferraccioli G.F. Curr. Opin. Anti-Inflamm. Immunomodulat. Invest. Drugs 2 (2000) 74
12. 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., Sweeney F.J., Taylor T.J., Trebino C.E., Abramov Y.A., Laird E.R., Volberg W.A., Zhou J., Bach J., and Lombardo F. Bioorg. Med. Chem. Lett. 16 (2006) 4339
13. Haddad J.J. Curr. Opin. Invest. Drugs 2 (2001) 1070
14. McClure K.F., Abramov Y.A., Laird E.R., Barberia J.T., Cai W., Carty T.J., Cortina S.R., Danley D.E., Dipesa A.J., Donahue K.M., Dombroski M.A., Elliott N.C., Gabel C.A., Han S., Hynes T.R., LeMotte P.K., Mansour M.N., Marr E.S., Letavic M.A., Pandit J., Ripin D.B., Sweeney F.J., Tan D., and Tao Y. J. Med. Chem. 48 (2005) 5728
15. Hirano M., Yakabe S., Monobe H., and Morimoto T. J. Chem. Res. (1998) 472
16. Firouzabadi H., and Karimi B. Synthesis (1999) 500
17. 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.
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. 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.
19. Compounds 48-50 were separated from a mixture of regioisomers, in poor yield, by treating 3 with NBS, dichloroacetic acid in 1,2-dichloroethane at 50 °C. Treating 49 with NBS, dibromoacetic acid in 1,2-dichloroethane at 50 °C gave 51, also in modest yield.
20. Xing L., Shieh H.S., Selness S.R., Devraj R.V., Walker J.K., Devadas B., Hope H.R., Compton R.P., Schindler J.F., Hirsch J.L., Benson A.G., Kurumbail R.G., Stegeman R.A., Williams J.M., Broadus Z.W., and Monahan J.B. Biochemistry 48 (2009) 6402
21. Fitzgerald C.E., Patel S.B., Becker J.W., Cameron P.M., Zaller D., Pilounis V.B., O'Keefe S.J., and Scapin G. Nat. Struct. Biol. 10 (2003) 764
22. Full disclosure of chemistry methods is made in the following patents: Rucker, P. V.; Jerome, K. D.; Selness, S. R.; Baldus, J. E.; Xing, L. PCT Int. Appl. 2006, 141 p, WO 2006018735.
23. Rucker, P. V.; Jerome, K. D.; Selness, S. R.; Baldus, J. E.; Xing, L. PCT Int. Appl. 2006, 161 p, WO 2006018727.
24. Kaminski Z.J. Synthesis 10 (1987) 917
25. The atomic coordinates for the X-ray structure of p38α in complex with 61 have been deposited in the RCSB: rcsb id code-RCSB055916; PDB code-3KF7.