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.
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.
D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002994:Clofibrate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives*; D051381:Rats; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D007783:Lactones; D014280:Triglycerides; D002784:Cholesterol; D002994:Clofibrate; D008798:Mevalonic Acid