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Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase |
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| Authors: | Selness Shaun R Boehm Terri L Walker John K Devadas Balekudru Durley Richard C Kurumbail Ravi Shieh Huey Xing Li Hepperle Michael Rucker Paul V Jerome Kevin D Benson Alan G Marrufo Laura D Madsen Heather M Hitchcock Jeff Owen Tom J Christie Lance Promo Michele A Hickory Brian S Alvira Edgardo Naing Win Blevis-Bal Radhika Devraj Rajesh V Messing Dean Schindler John F Hirsch Jeffrey Saabye Matthew Bonar Sheri Webb Elizabeth Anderson Gary Monahan Joseph B |
| Affiliation: | a Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA b Structural and Computational Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 3017, USA c Department of Pharmcokinetics and Drug Metabolism, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA d Inflammation Biology, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA |
| Abstract: | 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. |
| Keywords: | p38 kinase Inflammation Rheumatoid arthritis TNFα Pyridinones |
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