AbstractLinogliride (McN‐3935) [N‐(1‐methyl‐2‐pyrrolidinylidene)‐N'‐phenyl‐4‐morpholinecarboximidamide] was selected for clinical evaluation as a potential orally effective hypoglycemic agent for treatment of noninsulin‐dependent diabetes mellitus. Linogliride is structurally unrelated to sulfonylureas and biguanides. It produced a dose‐dependent hypoglycemic effect in nondiabetic rats, mice, and dogs. The minimum effective oral doses that lowered fasting blood glucose levels and improved glucose tolerance were 1–5 mg/kg. Comparison of the dose‐response curves from fasting rat studies showed linogliride to be approximately two times more potent than the related compound pirogliride and approximately eight times more potent than tolbutamide. Tolerance to its hypoglycemic effect did not develop in rat and dog 3‐day repeat dose studies. Linogliride did not alter plasma lactic acid levels in normal and streptozotocin‐induced diabetic rats, and it improved glucose tolerance whether the glucose was administered orally or parenterally. In nondiabetic rats and dogs, decreases in fasting blood glucose levels following linogliride administration were associated with elevated (two‐ to fourfold) plasma insulin concentrations. Linogliride was inactive in depancreatized diabetic dogs. In genetically diabetic (db/db) mice and streptozotocin‐induced diabetic rats, linogliride (25–100 mg/kg p.o.) produced variable, nondose‐dependent reductions of blood glucose levels, unlike the sulfonylureas, which were consistently ineffective in these diabetic rodent models. In conclusion, although the observed activity in diabetic rodent models is suggestive of a potential nonpancreatic mechanism, the experimental evidence to date indicates that the acute effectiveness of linogliride as a hypoglycemic agent is due primar