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

Autor:	and Lea M. Johnson, Bryan D. Anderson, Paul Lee, Miriam del Prado, C. Richard NevillJr., Sehila Pleite, Yong Wang, † Jaime Blanco-Urgoiti, Luisa M. Martín Cabrejas, Jeremy Schulenburg York, Robert M. Campbell, Deborah D. Giera, Michal Vieth, Jeffrey A. Wolos, Denis J. McCann, Chuan Shih, Li C. Li, Beatriz López de Uralde, Nicholas A. Magnus, Concepción Sánchez, Rosanne Bonjouklian, Richard M. Schultz, María José Lorite, Alfonso De Dios
Rok vydání:	2005
Předmět:	Lipopolysaccharides Models Molecular Anti-Inflammatory Agents Administration Oral Biological Availability Crystallography X-Ray Mitogen-Activated Protein Kinase 14 Mice chemistry.chemical_compound In vivo Drug Discovery Animals Humans Protein kinase A chemistry.chemical_classification Mice Inbred BALB C Binding Sites biology CYP3A4 Tumor Necrosis Factor-alpha Arthritis Experimental In vitro Rats Enzyme binding Enzyme chemistry Biochemistry Enzyme inhibitor Drug Design Macrophages Peritoneal biology.protein Molecular Medicine Benzimidazoles Collagen Lead compound
Zdroj:	Journal of Medicinal Chemistry. 48:2270-2273
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c105a28691f426c1b73e9b9ed314fcb https://doi.org/10.1021/jm048978k Zobrazit plný text záznamu