Synthesis and Hypolipidemic and Antidiabetogenic Activities of β,β,β',β'-Tetrasubstituted, Long-Chain Dioic Acids

Article abstract of DOI:10.1021/jm00129a010

β,β,β',β'-Tetrasubstituted, long-chain dioic acids of the general formula HOOC-C(XY)-C(R2)-Q-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 length (C12-C22), α,α'-substitutions (X,Y=H,F,Cl,Br,OH,CN), β,β'-substitutions (R=CH3,C6H5), and core substitutions 2, 1,4-C6H4<(CH2)3>2, 1,4-C6H4(CH=CHCH2)2, CH2(OCH2CH2)3OCH2)>.The most effective hypolipidemic-antidiabetogenic members of the series were α,α'-nonsubstituted, β,β'-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 proliferation in rats.