Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors

Bioorg Med Chem. 2014 Jun 15;22(12):3171-9. doi: 10.1016/j.bmc.2014.04.008. Epub 2014 Apr 13.

Abstract

Structure-activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility.

Keywords: Aqueous solubility; Diaryl amine; Kinesin spindle protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diphenylamine / chemistry*
  • Diphenylamine / pharmacology*
  • Humans
  • Kinesins / antagonists & inhibitors*
  • Kinesins / metabolism
  • Mitosis / drug effects*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Diphenylamine
  • Kinesins