Abstract
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha 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 strategy to address CyP3A4 liability is also described.
MeSH terms
-
Administration, Oral
-
Animals
-
Anti-Inflammatory Agents / chemical synthesis*
-
Anti-Inflammatory Agents / chemistry
-
Anti-Inflammatory Agents / pharmacology
-
Arthritis, Experimental / drug therapy
-
Benzimidazoles / chemical synthesis*
-
Benzimidazoles / chemistry
-
Benzimidazoles / pharmacology
-
Binding Sites
-
Biological Availability
-
Collagen
-
Crystallography, X-Ray
-
Drug Design
-
Humans
-
Lipopolysaccharides / pharmacology
-
Macrophages, Peritoneal / drug effects
-
Macrophages, Peritoneal / metabolism
-
Mice
-
Mice, Inbred BALB C
-
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
-
Mitogen-Activated Protein Kinase 14 / chemistry
-
Models, Molecular
-
Rats
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
-
Anti-Inflammatory Agents
-
Benzimidazoles
-
Lipopolysaccharides
-
Tumor Necrosis Factor-alpha
-
Collagen
-
Mitogen-Activated Protein Kinase 14