To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.
The antilipidemic properties of certain benzofuran-, 2,3-dihydrobenzofuran-, and 3(2H)-benzofuranone-2-carboxylate analogs of clofibrate in a hyperlipidemic rat model are described. The hyperlipidemia was induced by intraperitoneal injection of Triton WR-1339. The results were analyzed in light of structural modifications as well as the lipid solubility of substituted compounds as assessed by a consideration of calculated log P values. Comparisons are made between the activity of these compounds and the activity of related cyclic analogs previously reported. Among the various compounds tested, only the 5-C1 and phenylsybstituted dihydrobenzofurans were selective against elevated serum cholesterol levels in this animal model. The data presented support the hypothesis that the cholesterol and triglyceride lowering activity of clofibrate related analogs in this animal model may be separated through a consideration of log P, conformational, and electronic changes. The proposal is advanced that relatively minor structural modification of clofibrate related analogs may lead to compounds which are not only selective in the Triton model but also to compounds which are likely to exert their effects by differing modes of action.
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