Synthesis and hypolipidemic and antidiabetogenic activities of .beta.,.beta.,.beta.',.beta.'-tetrasubstituted, long-chain dioic acids

Abstract

.beta.,.beta.,.beta.,.beta.''-Tetrasubstituted, long-chain dioic acids of the general formula HOOC-C(XY)-C(R2)-Q-C(R2)-C(XY)-COOH have been synthesized and evaluated as hypotriglyceridemic-hypocholesterolemic agents in rats and as antidiabetogenic agents in ob/ob diabetic mice. The free carboxyl function of analogues of the series was mandatory for their hypolipidemic-antidiabetogenic effect while nonhydrolyzable diesters were inactive. Other structure-activity relationships were determined as a function of the overall chain lengthy (C12-C22), .alpha.,.alpha.''-substitutions (X,Y = H, F, Cl, Br, OH, CN), .beta.,.beta.''-substitutions (R = CH3, C6H5), and core substitutions [Q = (CH2)10, (CH2)4CH.dbd.CH(CH2)4, 1,4-C6H10[(CH2)3]2, 1,4-C6H4[(CH2)3]2, 1,4-C6H4(CH.dbd.CHCH2)2, CH2(OCH2CH2)3OCH2)]. The most effective hypolipidemic-antidiabetogenic members of the series were .alpha.,.alpha.''-nonsubtituted, .beta.,.beta.''-methyl-substituted analogues of 14-18-carbon chains having either a saturated aliphatic core or a 1,4-bis(propenyl)benzene core in the cis/trans configuration. The hypotriglyceridemic rather than the hypocholesterolemic capacity of members of the series was found to correlate with their respective capacities as liver peroxisomal proliferators in rats.