1. Design, synthesis and activity of a potent, selective series of N -aryl pyridinone inhibitors of p38 kinase
- Author
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Dean Messing, Brian S. Hickory, Alan G. Benson, Matthew J. Saabye, Jeff Hitchcock, Heather M. Madsen, Devadas Balekudru, Shaun R. Selness, Richard C. Durley, Laura D. Marrufo, Gary D. Anderson, Li Xing, Kevin D. Jerome, Michael Hepperle, Christie Lance Christopher, Rajesh V. Devraj, Elizabeth G. Webb, Thomas Owen, Ravi G. Kurumbail, Edgardo Alvira, Jeffrey L. Hirsch, Joseph B. Monahan, Paul V. Rucker, Boehm Terri L, Blevis-Bal Radhika M, Huey S. Shieh, John K. Walker, John F. Schindler, Michele A. Promo, Win Naing, and Sheri L. Bonar
- Subjects
Male ,Pyridones ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Chemical synthesis ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,Kinase ,Aryl ,Organic Chemistry ,Biological activity ,Rats ,Enzyme Activation ,Pyridazines ,Disease Models, Animal ,Pyrimidines ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,Mitogen-activated protein kinase ,Microsomes, Liver ,biology.protein ,Molecular Medicine - 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.
- Published
- 2011
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