Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus

J Med Chem. 1991 Jan;34(1):357-66. doi: 10.1021/jm00105a056.


A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl) ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33,(+)-(4R)-trans-2-(4-fluororphenyl)-5-(1-methylethyl)-N,3- diphenyl-1- [(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4- carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anticholesteremic Agents / chemical synthesis*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors*
  • Indicators and Reagents
  • Liver / enzymology
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Pyrones / chemical synthesis*
  • Pyrones / chemistry
  • Pyrones / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rats
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship


  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indicators and Reagents
  • Pyrones
  • Pyrroles