INHIBITORS OF CHOLESTEROL-BIOSYNTHESIS .2. 3,5-DIHYDROXY-7-(N-PYRROLYL)-6-HEPTENOATES, A NOVEL SERIES OF HMG-COA REDUCTASE INHIBITORS

A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl[-3,5-dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.