Comparison of hypocholesterolemic activity for cyclic analogs of clofibrate in normolipemic rats

Chronic administration of ethyl 2-methyl-2(4-chlorophenoxy)-propionate [clofibrate, CPIB], ethyl 6-cyclohexylchroman-2carboxylate, and ethyl 6-phenylchroman-2-carboxylate to normolipemic rats, in vivo, reduced serum cholesterol levels and inhibitid the activiry of hepatic 3-hydroxy-3methyl-glutaryl Coenzyme A. Only clofibrate was found to lower liver cholesterol content after pretreatment for 4 or 18 days. The cyclic analogs, ethyl 6-cholorochromone-2-carboxylate and 9-chloro-2,3-dihydro-5H-1,4-dioxepino [6,5-b] benzofuran were inaffective as cholesterol lowering agents in normolipemic rats. These findings indicate that appropriate modification of clofibrate can lead to the development of compounds which are selective and equally effective to clofibrate as potential hypocholesterolemic agents. Results obtained in these studies are also discussed in terms of the known structural requirements of biological activity for this series of cyclic analogs in the Triton WR-1339 hyperlipemic rat model and modes of action of the parent compound.