Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives

Chem Pharm Bull (Tokyo). 2011;59(10):1268-73. doi: 10.1248/cpb.59.1268.

Abstract

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / pharmacokinetics*
  • Acetamides / pharmacology*
  • Acetanilides / chemistry
  • Acyl Coenzyme A / antagonists & inhibitors*
  • Administration, Oral
  • Animals
  • Anticholesteremic Agents / chemical synthesis
  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / pharmacokinetics
  • Anticholesteremic Agents / pharmacology*
  • Apolipoproteins / metabolism
  • Atherosclerosis / metabolism*
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacokinetics*
  • Benzopyrans / pharmacology*
  • Cholesterol / metabolism
  • Coumarins / chemistry
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Structure-Activity Relationship

Substances

  • 2-(7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl)-N-(4-chloro-2-(trifluoromethyl)phenyl)acetamide
  • Acetamides
  • Acetanilides
  • Acyl Coenzyme A
  • Anticholesteremic Agents
  • Apolipoproteins
  • Benzopyrans
  • Coumarins
  • Enzyme Inhibitors
  • 4-phenylcoumarin
  • Cholesterol
  • acetanilide