Inhibitors of cholesterol biosynthesis. 2. 3,5-Dihydroxy-7-(N-pyrrolyl)-6-heptenoates, a novel series of HMG-CoA reductase inhibitors

• Published in: Journal of medicinal chemistry 1993-11, Vol.36 (23), p.3658-3662
• Main Authors: Procopiou, Panayiotis A, Draper, Christopher D, Hutson, Julie L, Inglis, Graham G. A, Ross, Barry C, Watson, Nigel S
• Format: Article
• Language: English
• Subjects: Carcinoma, Hepatocellular - metabolism; Cholesterol - biosynthesis; Humans; Hydroxy Acids - chemical synthesis; Hydroxy Acids - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver Neoplasms - metabolism; Lovastatin - pharmacology; Molecular Structure; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00075a021

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.