Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors

Bioorg Med Chem. 2004 Nov 15;12(22):5899-908. doi: 10.1016/j.bmc.2004.08.033.

Abstract

Squalene synthase inhibitors are potentially superior hypolipidemic agents. We synthesized novel propylamine derivatives, as well as evaluated their ability to inhibit squalene synthase and their lipid-lowering effects in rats. 1-Allyl-2-[3-(benzylamino)propoxy]-9H-carbazole (YM-75440) demonstrated potent inhibition of the enzyme derived from HepG2 cells with an IC(50) value of 63 nM. It significantly reduced both plasma total cholesterol and plasma triglyceride levels following oral dosing to rats with a reduced tendency to elevate plasma transaminase levels.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis*
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism
  • Humans
  • Male
  • Propylamines / administration & dosage
  • Propylamines / chemical synthesis*
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley

Substances

  • Enzyme Inhibitors
  • Propylamines
  • Farnesyl-Diphosphate Farnesyltransferase