A novel, orally effective hypoglycemic agent, SaRI 59–801, in laboratory animals

Abstract

AbstractSaRl 59‐801 (59‐801) (α‐[dimethylaminomethyl]‐2‐[3‐ethyl‐5‐methyl‐4‐isoxazolyl]‐1H‐indole‐3‐methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2‐hr hypoglycemic ED25 in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED50 of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59‐801 to fasting rats (ED25 = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59‐801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1‐hr pretreatment with 59‐801 (ED50 = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED25 of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db+/db+) mice, 59‐801 was more potent in producing hypoglycemia (ED25 = 47 mg/kg) than their lean littermates (ED25 = 131 mg/kg). In alloxan‐diabetic rats or streptozotocin‐diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β‐cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59‐801.