Discovery and structure-activity-relationship study of novel conformationally restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5262-5266. doi: 10.1016/j.bmcl.2017.10.029. Epub 2017 Oct 16.

Abstract

The discovery and optimization of various of indane amides 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, favorable PK properties and great selectivity against IDH1wt and IDH2R140Q.

Keywords: IDH1 inhibitor; Indane amide; Structure-based rational design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indans / chemical synthesis
  • Indans / chemistry
  • Indans / pharmacology*
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Mice
  • Microsomes / chemistry
  • Microsomes / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indans
  • Isocitrate Dehydrogenase
  • IDH1 protein, human