3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta

J Med Chem. 2009 Dec 10;52(23):7618-30. doi: 10.1021/jm9005127.

Abstract

In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38alpha (IC(50) = 0.45 microM) and CK1delta (IC(50) = 0.23 microM). Because only a few effective small molecule inhibitors of CK1 have been described so far, we aimed to develop this structural class toward specific agents. Molecular modeling studies comparing p38alpha/CK1delta suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC(50) p38alpha = 0.006 microM; IC(50) CK1delta = 1.6 microM), 13 (IC(50) p38alpha = 2.52 microM; IC(50) CK1delta = 0.033 microM), 17 (IC(50) p38alpha = 0.019 microM; IC(50) CK1delta = 0.004 microM; IC(50) CK1epsilon = 0.073 microM), and 18 (CKP138) (IC(50) p38alpha = 0.041 microM; IC(50) CK1delta = 0.005 microM; IC(50) CK1epsilon = 0.447 microM) possessing differentiated specificity. Selected compounds were profiled over 76 kinases and evaluation of their cellular efficacy showed 18 (CKP138) to be a highly potent and dual-specific inhibitor of CK1delta and p38alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding, Competitive
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Idelta / chemistry
  • Casein Kinase Idelta / genetics
  • Casein Kinase Idelta / metabolism
  • Cell Line
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Isoxazoles / chemistry*
  • Isoxazoles / metabolism
  • Isoxazoles / pharmacology*
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / chemistry
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Rats
  • Trophoblasts / cytology
  • Trophoblasts / drug effects

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Isoxazoles
  • imidazole
  • Adenosine Triphosphate
  • Casein Kinase Idelta
  • Mitogen-Activated Protein Kinase 14