Synthesis and antilipidemic properties of cis-7-chloro-3a,8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, a tricyclic clofibrate related lactone having a structural resemblance to mevalonolactone

• Published in: Journal of medicinal chemistry 1976-10, Vol.19 (10), p.1214-1220
• Main Authors: Witiak, Donald T, Kuwano, Eiichi, Feller, Dennis R, Baldwin, John R, Newman, Howard A. I, Sankarappa, Shankar K
• Format: Article
• Language: English
• Subjects: Animals; Cholesterol - blood; Cholesterol - metabolism; Clofibrate - analogs & derivatives; Clofibrate - chemical synthesis; Clofibrate - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias - blood; Hyperlipidemias - metabolism; Hypolipidemic Agents - chemical synthesis; Lactones - chemical synthesis; Liver - enzymology; Liver - metabolism; Male; Mevalonic Acid - analogs & derivatives; Rats; Structure-Activity Relationship; Triglycerides - blood; Triglycerides - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00232a009

The synthesis for the title lactone 2, designed to be an antagonist of the enzyme HMG-CoA reductase (E.C.1.1.1.34), is described. Lactone 2, its synthetic tricyclic hemiacetal precursor 4, and clofibrate were investigated for their antilipidemic activity in 7-day treated normal and in Triton WR-1339 induced hyperlipidemic male Sprague-Dawley rats. After 7-day drug administration to normal rats, lactone 2 was less effective than clofibrate in lowering HMG-CoA reductase activity and serum cholesterol; however, unlike clofibrate, lactone 2 did not increase liver weight or liver-body weight ratio or lower serum triglycerides. Since hemiacetal 4 selectively influenced triglycerides in normal animals, lactone 2 and hemiacetal 4 appear to have differential hypolipidemic effects. In the Triton hyperlipidemic model 2 and 4 lowered elevated triglycerides; only 4 significantly reduced elevated cholesterol levels; but neither 2 nor 4 was as effective as clofibrate. Differences in the observed antilipidemic properties for clofibrate, 2, and 4 in the two animal models are discussed. On the basis of preliminary biological data described in this article it is concluded that tricyclic analogues 2 and 4 represent reasonable leads for the development of new antilipidemic agents.