title: HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts.
abstract: Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5- dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 microM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869.
authors.forename: P J
authors.initials: PJ
authors.lastname: Connolly
authors.forename: C D
authors.initials: CD
authors.lastname: Westin
authors.forename: D A
authors.initials: DA
authors.lastname: Loughney
authors.forename: L K
authors.initials: LK
authors.lastname: Minor
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D002784:Cholesterol / Q000096:biosynthesis; D006880:Hydroxy Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology; D008148:Lovastatin / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000085:Acetates; D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007191:Indazoles; C084472:7-(7-((1,1'-biphenyl-4-yl)methyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-3,5-dihydroxy-6-heptenoic acid; D002784:Cholesterol; D008148:Lovastatin