Syntheses and Hypoglycemic Activities of Ethyl Esters and Various Amides of ω-Guanidino Fatty Acids with Medium Chain Length

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Abstract
The .omega.-guanidino fatty acids C6-C12 were prepared by amidination of the corresponding .omega.-amino acids. .omega.-Amino acids C7-C10 which are not available commercially were obtained by use of Hofmann degradation of the next higher dicarboxylic monoamid monoethyl esters. For use in biological tests, the .omega.-guanidino fatty acids were converted into ethyl esters, dimethylamides, sometimes also into methyl- or diethylamides. In isolated fat cells these compounds inhibit glucose oxidation. The inhibition increases with increasing chain length. For example, glucose oxidation (control 100%) is diminished by the dimethylamides of 9-guanidinononanoic acid to 70%, of 10-guanidinodecanoic acid to 62% of 11-guanidinoundecanoic acid to 17% and of 12-guanidinodecanoic acid to 12%. The same compounds, except the ethyl esters, depress the blood glucose levels in mice after i.p. injection. Blood glucose levels between 30 and 10 mg/100 ml are reached and convulsions are observed. In the mice fall test, approximately 15-30 min post injection, the mice fall down; the blood glucose values of the fallen mice are hypoglycemic. The toxicity of the compounds examined is remarkably high; LD/mouse (20 g) is 3-5 mg for the dimethylamides. It is obvious that a relationship exists between the inhibition of glucose oxidation in adipocytes and the depression of blood glucose level. The stronger the inhibition, the stronger the blood glucose lowering effect.

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