HYPOGLYCEMIC ACTIVITY AND TOXICITY OF 4-ISOXAZOLYLPYRIDINIUM SALTS AND PHENFORMIN IN NORMAL MICE

1-Methyl-4-(3-methyl-5-isoxazolyl)-pyridinium chloride (I) was reported to be an orally active hypoglycemic in several animal species and alloxan-hyperglycemic mice and rats. Studies were conducted to evaluate hypoglycemic potency and toxicity of structural analogs in normal mice. Of thirteen compounds tested, nine were less potent than I, and two were equipotent to I. Two had no hypoglycemic activity. The presence of the quaternary nitrogen in the pyridinium ring was necessary for hypoglycemic activity. Increase in length of the carbon chain on the pyridyl nitrogen or absence of an alkyl group on the three carbon of the isoxazole ring decreased hypoglycemic activity. Two compounds were less toxic, one equitoxic, and six more toxic than I. On the basis of these studies, I had the best therapeutic index ( LD50 ED50) in normal mice. A comparison to the clinically active hypoglycemic agent, phenformin, was also conducted. Compound I was more potent and less toxic than phenformin in normal mice, having a 5-fold greater margin of safety. © 1969.