Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase

  • Bioorg Med Chem Lett. 2007 Mar 15;17(6):1679-83. doi: 10.1016/j.bmcl.2006.12.086.
I Wayne Cheney  1 ,  Shunqi Yan ,  Todd Appleby ,  Heli Walker ,  Todd Vo ,  Nanhua Yao ,  Robert Hamatake ,  Zhi Hong ,  Jim Z Wu
Affiliations
  • 1. Valeant Pharmaceuticals Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. [email protected]
PMID: 17251021 DOI: 10.1016/j.bmcl.2006.12.086
Abstract

A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC(50)=50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R(1) phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.

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