Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents

Bioorg Med Chem Lett. 2003 Apr 7;13(7):1337-40. doi: 10.1016/s0960-894x(03)00116-1.

Abstract

A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.

MeSH terms

  • Animals
  • Anticholesteremic Agents / chemical synthesis*
  • Anticholesteremic Agents / pharmacology*
  • Carrier Proteins / antagonists & inhibitors*
  • Cholesterol, VLDL / metabolism
  • Cricetinae
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Molecular Conformation
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Anticholesteremic Agents
  • Carrier Proteins
  • Cholesterol, VLDL
  • Organophosphonates
  • microsomal triglyceride transfer protein