Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6--2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus

Article abstract of DOI:10.1021/jm00105a056

A series of trans-tetrahydro-4-hydroxy-6-<2-(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 subtantially 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-fluorophenyl)-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.