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

J Med Chem. 1989 Sep;32(9):2072-84. doi: 10.1021/jm00129a010.


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.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Chemical Phenomena
  • Chemistry
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / metabolism
  • Dicarboxylic Acids / chemical synthesis*
  • Dicarboxylic Acids / pharmacology
  • Female
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacology
  • Hypolipidemic Agents / chemical synthesis*
  • Hypolipidemic Agents / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microbodies / drug effects
  • Microbodies / metabolism
  • Obesity
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship


  • Blood Glucose
  • Dicarboxylic Acids
  • Hypoglycemic Agents
  • Hypolipidemic Agents