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Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase |
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| Authors: | Shaun R. Selness Rajesh V. Devraj Joseph B. Monahan Terri L. Boehm John K. Walker Balekudru Devadas Richard C. Durley Ravi Kurumbail Huey Shieh Li Xing Michael Hepperle Paul V. Rucker Kevin D. Jerome Alan G. Benson Laura D. Marrufo Heather M. Madsen Jeff Hitchcock Tom J. Owen Lance Christie Michele A. Promo Radhika Blevis-Bal |
| Affiliation: | 1. Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA;2. Inflammation Biology, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA;3. Structural and Computational Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA |
| Abstract: | The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38α. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation. |
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