OMEGA-SUBSTITUTED ALKYL CARBOXYLIC-ACIDS AS ANTIDIABETIC AND LIPID-LOWERING AGENTS

In screening experiments certain omega-substituted alkyl carboxylic ac ids were found to produce an increase in insulin-stimulated C-14-aceta te 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 struct ures of the w-substituted alkyl carboxylic acids with insulin-potentia ting effects correspond to the general formula ring-spacer-COOH. A clo se structure-activity relationship was observed. The most potent compo und in ob/ob mice was 3e, which normalized blood glucose as well as hy perinsulinaemia and lowered serum triglycerides and cholesterol by 52% and 37%, respectively. On the basis of these results, omega-substitut ed alkyl carboxylic acids are interesting as a new class of oral antid iabetic agents with insulin-sensitizing and lipid-lowering activity. ( C) Elsevier, Paris.