ω-Substituted alkyl carboxylic acids as antidiabetic and lipid-lowering agents

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Abstract

In screening experiments certain ω-substituted alkyl carboxylic acids, were found to produce an increase in insulin-stimulated 14C-acetate incorporation into triglycerides, which may indicate an improvement in the action of insulin. Antidiabetic and lipid-lowering properties in genetically diabetic ob/ob mice demonstrated the in vivo relevance of the insulin-potentiating effects seen in vitro. The chemical structures of the ω-substituted alkyl carboxylic acids with insulin-potentiating effects correspond to the general formula ring-spacer-COOH. A close structure-activity relationship was observed. The most potent compound in ob/ob mice was 3e, which normalized blood glucose as well as hyperinsulinaemia and lowered serum triglycerides and cholesterol by 52% and 37%, respectively. On the basis of these results, ω-substituted alkyl carboxylic acids are interesting as a new class of oral antidiabetic agents with insulin-sensitizing and lipid-lowering activity.

References (36)

  • AndersonS. et al.

    J. Diab. Comp.

    (1995)
  • FujiwaraT. et al.

    Metabolism

    (1991)
  • LongS.D. et al.

    J. Biol. Chem.

    (1996)
  • LehmannJ.M. et al.

    J. Biol. Chem.

    (1995)
  • LeuteneggerM.

    Curr. Ther. Res.

    (1997)
  • SpadyD.K. et al.

    J. Lipid Res.

    (1983)
  • AndersenJ.M. et al.

    J. Lipid Res.

    (1979)
  • HerbergL. et al.

    Metabolism

    (1977)
  • DeFronzoR.A.

    Diabetologia

    (1992)
  • TrischittaV. et al.

    Diabetes/Metab. Rev.

    (1997)
  • DeFronzoR.A. et al.

    Diabetes Care

    (1991)
  • ReavenG.M.

    Diabetes

    (1988)
  • SaltielA.R. et al.

    Diabetes

    (1996)
  • PantenU.

    Diabetes Stoffwechsel

    (1992)
  • KlipA. et al.

    Diabetes Care

    (1990)
  • ChangA.Y. et al.

    Diabetes

    (1983)
  • SohodaT.

    Arzneim. Forsch.

    (1990)
  • StevensonR.W.

    Diabetes

    (1990)
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