Design of potent and selective 2-aminobenzimidazole-based p38α MAP kinase inhibitors with excellent in vivo efficacy

…, C Shih, B López de Uralde, C Sánchez…

Index: De Dios, Alfonso; Shih, Chuan; Lopez De Uralde, Beatriz; Sanchez, Concepcion; Del Prado, Miriam; Martin Cabrejas, Luisa M.; Pleite, Sehila; Blanco-Urgoiti, Jaime; Lorite, Maria Jose; Nevill Jr., C. Richard; Bonjouklian, Rosanne; York, Jeremy; Vieth, Michal; Wang, Yong; Magnus, Nicholas; Campbell, Robert M.; Anderson, Bryan D.; McCann, Denis J.; Giera, Deborah D.; Lee, Paul A.; Schultz, Richard M.; Li, Li C.; Johnson, Lea M.; Wolos, Jeffrey A. Journal of Medicinal Chemistry, 2005 , vol. 48, # 7 p. 2270 - 2273

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Citation Number: 54

Abstract

We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38α inhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFα release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR ...