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

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, 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

Index: Bioorg. Med. Chem. Lett. 21(13) , 4059-65, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.