- Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.
Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.
Bioorganic & medicinal chemistry letters (2011-06-07)
Shaun R Selness, 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, Brian S Hickory, Edgardo Alvira, Win Naing, Radhika Blevis-Bal, Rajesh V Devraj, Dean Messing, John F Schindler, Jeffrey Hirsch, Matthew Saabye, Sheri Bonar, Elizabeth Webb, Gary Anderson, Joseph B Monahan
PMID21640588
摘要
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.
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