Novel indolizine derivatives with unprecedented inhibitory activity on human farnesyltransferase

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5777-5781. doi: 10.1016/j.bmcl.2014.10.044. Epub 2014 Oct 22.

Abstract

The rational structural modification of new substituted indolizin-3-yl(phenyl)methanones 1a-i, 2a-i and 3a-i has greatly improved human farnesyltransferase inhibition. The para-bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC50 value of 1.3±0.2 μM. The amidic series 1a-i proves to be the most promising for future modulations, particularly at the triple bond level.

Keywords: Activated ester; Butynyl ester; Farnesyltransferase inhibitor; Indolizine; Propargyl amide; Propargyl ester.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Humans
  • Indolizines / chemical synthesis
  • Indolizines / chemistry*
  • Indolizines / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indolizines
  • indolizine
  • Farnesyltranstransferase