Design, synthesis and activity of a potent, selective series of N -aryl pyridinone inhibitors of p38 kinase

Autor:	Dean Messing, Brian S. Hickory, Alan G. Benson, Matthew J. Saabye, Jeff Hitchcock, Heather M. Madsen, Devadas Balekudru, Shaun R. Selness, Richard C. Durley, Laura D. Marrufo, Gary D. Anderson, Li Xing, Kevin D. Jerome, Michael Hepperle, Christie Lance Christopher, Rajesh V. Devraj, Elizabeth G. Webb, Thomas Owen, Ravi G. Kurumbail, Edgardo Alvira, Jeffrey L. Hirsch, Joseph B. Monahan, Paul V. Rucker, Boehm Terri L, Blevis-Bal Radhika M, Huey S. Shieh, John K. Walker, John F. Schindler, Michele A. Promo, Win Naing, Sheri L. Bonar
Rok vydání:	2011
Předmět:	Male Pyridones medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Carboxamide p38 Mitogen-Activated Protein Kinases Biochemistry Chemical synthesis Rats Sprague-Dawley Inhibitory Concentration 50 chemistry.chemical_compound Drug Discovery medicine Animals Humans Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure biology Kinase Aryl Organic Chemistry Biological activity Rats Enzyme Activation Pyridazines Disease Models Animal Pyrimidines Enzyme chemistry Enzyme inhibitor Drug Design Mitogen-activated protein kinase Microsomes Liver biology.protein Molecular Medicine
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 21:4059-4065
ISSN:	0960-894X
Popis:	A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b57328f6e5ea96fc972d684f2e92281c https://doi.org/10.1016/j.bmcl.2011.04.120 Zobrazit plný text záznamu Full Text from ScienceDirect