Discovery of novel type II c-Met inhibitors based on BMS-777607

Eur J Med Chem. 2014 Jun 10:80:254-66. doi: 10.1016/j.ejmech.2014.04.056. Epub 2014 Apr 21.

Abstract

Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.

Keywords: Kinase inhibitor; Synthesis; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacology*
  • Cell Line, Tumor
  • Drug Discovery*
  • Humans
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  • Protein Kinase Inhibitors
  • Pyridones
  • Proto-Oncogene Proteins c-met