Synthesis and hypolipidemic and antidiabetogenic activities of beta,beta,beta',beta'-tetrasubstituted, long-chain dioic acids.
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 length (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 = CH(CH2)4, 1,4-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 alpha,alpha'-nonsubstituted, 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.
Bar-Tana
J
J
Department of Biochemistry, Hebrew University, Jerusalem, Israel.
Ben-Shoshan
S
S
Blum
J
J
Migron
Y
Y
Hertz
R
R
Pill
J
J
Rose-Khan
G
G
Witte
E C
EC
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D055598:Chemical Phenomena; D002621:Chemistry; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D009765:Obesity; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D003998:Dicarboxylic Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents