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.
Procopiou
P A
PA
Department of Medicinal Chemistry, Glaxo Group Research Ltd., Greenford, Middlesex, United Kingdom.
Draper
C D
CD
Hutson
J L
JL
Inglis
G G
GG
Ross
B C
BC
Watson
N S
NS
D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D006801:Humans; D006880:Hydroxy Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008113:Liver Neoplasms / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C084470:7-(3-bromo-4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-pyrrol-1-yl)-3,5-dihydroxy-6-heptenoic acid methyl ester; D002784:Cholesterol; D008148:Lovastatin