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

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Abstract
The synthesis for cis-7-chloro-3a,8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, designed to be an antagonist of the enzyme HMG[3-hydroxy-3-methylglutaryl]-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 [tyloxypal] 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 2 animal models are discussed. Tricyclic analogues 2 and 4 appear to represent reasonable leads for the development of new antilipidemic agents.