Synthesis and Biological Evaluation of Dihydroeptastatin, a Novel Inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase

J Med Chem. 1992 Sep 4;35(18):3388-93. doi: 10.1021/jm00096a015.

Abstract

The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.

MeSH terms

  • Animals
  • Hydroxymethylglutaryl CoA Reductases / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors*
  • Pravastatin / analogs & derivatives*
  • Pravastatin / chemical synthesis
  • Pravastatin / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • dihydroeptastatin
  • Hydroxymethylglutaryl CoA Reductases
  • Pravastatin