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Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase

2011; Elsevier BV; Volume: 21; Issue: 13 Linguagem: Inglês

10.1016/j.bmcl.2011.04.121

1464-3405

Shaun R. Selness, Rajesh Devraj, Balekudru Devadas, John K. Walker, Terri L. Boehm, Richard C. Durley, H.-S. Shieh, Lei Xing, Paul V. Rucker, Kevin D. Jerome, Alan G. Benson, Laura D. Marrufo, Heather M. Madsen, Jeff Hitchcock, Tom J. Owen, Lance C. Christie, Michele A. Promo, Brian S. Hickory, Edgardo Alvira, Win Naing, Radhika Blevis-Bal, Dean Messing, Jerry Z. Yang, Michael K. Mao, Gopi Yalamanchili, Richard Vonder Embse, J. Hirsch, Matthew J. Saabye, Sheri L. Bonar, Elizabeth Webb, Gary D. Anderson, Joseph B. Monahan,

Cytokine Signaling Pathways and Interactions

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.