Discovery and structure-activity-relationship study of novel imidazole cyclopropyl amine analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3808-3812. doi: 10.1016/j.bmcl.2018.07.002. Epub 2018 Jul 4.

Abstract

The discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties.

Keywords: IDH1 inhibitor; Imidazole cyclopropyl amine; Structure-based rational design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry
  • Amines / metabolism
  • Amines / pharmacokinetics
  • Amines / pharmacology
  • Animals
  • Cell Line
  • Drug Design*
  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Mutation
  • Rats
  • Structure-Activity Relationship

Substances

  • Amines
  • Enzyme Inhibitors
  • Imidazoles
  • Isocitrate Dehydrogenase
  • IDH1 protein, human