Synthesis and Hypolipidemic and Antidiabetogenic Activities of β,β,β',β'-tetrasubstituted, Long-chain Dioic Acids

,β,β',β'-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 length (C₁₂-C₂2), α,α'-substitutions (X, Y = H, F, Cl, Br, OH, CN), β,β'-substitutions (R = CH₃, C₆H₅), and core subtitutions [Q = (CH₂)₁₀, (CH₂)₄CH=CH(CH₂)₄, l,4-C₆H₁₀[(CH₂)₃]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 a,a'-nonsubstituted, β,β'-methyl-substituted analogues of 14-18-carbon chains having either a saturated aliphatic core or a l,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.