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SaRl 59-801 (59-801) (c-, 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 EDz5 in fasting mice was 110 mglkg; the plasma insulin levels were increased, with an ED50 of 47 mglkg.Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED25 = 86 mglkg), while plasma insulin was elevated by 62% at 100 mglkg. 59-801caused 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 (ED5, = 37 mglkg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats.ln monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mglkg and an ED25 of 33 mglkg for a period of 6 hr after oral administration. In genetically diabetic (db+ldb+) mice, 59-801 was more potent in producing hypoglycemia (ED25 = 47 mglkg) than their lean littermates (ED25 = 131 mglkg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mglkg, but at 400 mglkg, it caused reduction of blood glucose levels of 29-39 and 21%, respectively, possibly the result of stimulation of residual P-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.

The new oral hypoglycemic agent SDZ 51641 was evaluated in nondiabetic rats and a rat model of human non-insulin-dependent diabetes mellitus. Diabetes was induced with a single injection of 37.5 mg/kg streptozocin, and the rats exhibited hyperglycemia in the fed state with normal insulin levels. Treatment of nondiabetic animals with 100 mg/kg SDZ 51641 given orally significantly decreased serum glucose and ketone levels within 4 h without affecting insulin levels. Nonesterified fatty acids increased more than twofold during the same period. Its effect on ketone and fatty acid levels suggests that SDZ 51641 acts as an inhibitor of fatty acid oxidation. Diabetic rats treated with SDZ 51641 exhibited a significant acute hypoglycemic response, which was more pronounced after 3 days of treatment. The compound also significantly decreased serum cholesterol and triglyceride levels 27 and 53%, respectively. When endogenous hepatic glucose production was assessed in nondiabetic and diabetic animals via continuous infusion of [3-3H]glucose, we found that hepatic glucose production was elevated 43% in diabetic compared with control animals. When diabetic rats were treated with 100 mg/kg SDZ 51641, hepatic glucose production decreased to normal levels within 6 h. Hyperinsulinemic-euglycemic clamp studies indicated that SDZ 51641 had no effect on insulin-stimulated glucose utilization. Measurement of [1-14C]oleate oxidation in isolated hepatocytes demonstrated that SDZ 51641 inhibited long-chain fatty acid oxidation in a concentration-dependent manner. The compound was ineffective at inhibiting long-chain fatty acid oxidation in epitrochlearis or soleus muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

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The glucose absorption inhibitors, Phenformin and 3‐phenylpropylaminoguanide HCl (SaH 43–522) have different effects on hepatic gluconeogenesis. Unlike phenformin, 43–522 in vivo does not inhibit hepatic gluconeogenesis; inhibition occurred only when 43–522 was added directly to a liver perfusion system. This suggests that when 43–522 is administered in vivo it is metabolized to an agent that does not inhibit hepatic gluconeogenesis whereas phenformin is not metabolized, and does inhibit gluconeogenesis. This is an advantage of 43–522 since it thereby specifically inhibits intestinal glucose absorption without a potential hypoglycaemic effect due to the suppression of gluconeogenesis.