2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1γ) inhibitors

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5392-5. doi: 10.1016/j.bmcl.2012.07.046. Epub 2012 Jul 20.

Abstract

Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.

MeSH terms

  • Animals
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Binding Sites
  • Casein Kinase I / antagonists & inhibitors*
  • Casein Kinase I / chemistry
  • Casein Kinase I / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • beta Catenin / metabolism

Substances

  • Benzimidazoles
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • beta Catenin
  • Casein Kinase I