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Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase |
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| Authors: | Selness Shaun R Devraj Rajesh V Devadas Balekudru Walker John K Boehm Terri L Durley Richard C Shieh Huey Xing Li 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 Messing Dean Yang Jerry Mao Michael K Yalamanchili Gopi Vonder Embse Richard Hirsch Jeffrey Saabye Matthew Bonar Sheri Webb Elizabeth Anderson Gary Monahan Joseph B |
| Institution: | a Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States b Structural and Computational Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States c Department of Pharmcokinetics and Drug Metabolism, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States d Department of Pharmaceutical Sciences, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States e Inflammation Biology, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States |
| Abstract: | The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (−)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (−)-4a are described. |
| Keywords: | p38 Kinase Inflammation Rheumatoid arthritis TNFα Pyridinones PH-797804 Atropisomers |
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