Design of Potent and Selective 2-Aminobenzimidazole-Based p38α MAP Kinase Inhibitors with Excellent in Vivo Efficacy

• Published in: Journal of medicinal chemistry Vol. 48; no. 7; pp. 2270 - 2273
• Main Authors: de Dios, Alfonso, Shih, Chuan, López de Uralde, Beatriz, Sánchez, Concepción, del Prado, Miriam, Martín Cabrejas, Luisa M, Pleite, Sehila, Blanco-Urgoiti, Jaime, Lorite, María José, Nevill, 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, Johnson, Lea M, Wolos, Jeffrey A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07-04-2005
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Medical sciences; Pharmacology. Drug treatments; Rat; Enzyme; Transferases; Rodentia; Antiinflammatory agent; Oral administration; Enzyme inhibitor; Mitogen-activated protein kinase; Selectivity; In vitro; In vivo; Signal transduction; Vertebrata; Mammalia; Structure activity relation; Protein kinase; Animal; Fluorine Organic compounds; Antirheumatic agent; Pharmacokinetics; Chemical synthesis; Tumor necrosis factor α
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm048978k

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 strategy to address CyP3A4 liability is also described.