3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 9. The Synthesis and Biological Evaluation of Novel Simvastatin Analogs

J Med Chem. 1992 Oct 16;35(21):3813-21. doi: 10.1021/jm00099a009.

Abstract

Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. Oral activity of these compounds was determined in an acute rat model and a three-week study in cholestyramine-primed dogs. Compounds were identified that possessed in vitro and in vivo activity comparable to that of simvastatin.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticholesteremic Agents / chemical synthesis*
  • Anticholesteremic Agents / pharmacology
  • Disease Models, Animal
  • Dogs
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors*
  • Hypercholesterolemia / drug therapy
  • Lovastatin / analogs & derivatives*
  • Lovastatin / chemical synthesis
  • Lovastatin / pharmacology
  • Lovastatin / therapeutic use
  • Magnetic Resonance Spectroscopy
  • Rats
  • Simvastatin
  • Structure-Activity Relationship

Substances

  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lovastatin
  • Simvastatin