Takao Ikenoue

Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (−)-N-(trans-4-isopropylcyclohexane-carbonyl)-d-phenylalanine (A-4166)

(−)‐N‐(trans‐4‐isopropylcyclohexanecarbonyl)‐d‐phenylalanine (A‐4166), a novel oral hypoglycaemic agent is a non‐sulphonylurea insulin secretagogue. We investigated the insulin‐releasing action and hypoglycaemic effect of A‐4166 compared to sulphonylureas in vitro and in vivo. A‐4166 stimulated insulin secretion from rat freshly isolated pancreatic islets at concentrations from 3×10‐6m to 3×10‐4m in the presence of 2.8 mm glucose. There was no obvious difference in glucose dependency between the insulinotropic effect of A‐4166 and that of glibenclamide, and no additive or synergistic effect was observed between these two drugs. A‐4166 displaced [3H]‐glibenclamide bound to intact HIT‐T15 cells in a concentration‐dependent manner. The Ki value was 4.34±0.04×10−7m, and the displacement potency of A‐4166 was between that of glibenclamide and tolbutamide, being similar to that of gliclazide. In fasted beagle dogs, A‐4166 showed a dose‐dependent hypoglycaemic effect after oral administration over the range 1 to 10 mg kg−1. The hypoglycaemic action of A‐4166 showed an earlier onset and a shorter duration than that of sulphonylureas. Simultaneous measurement of plasma insulin levels revealed that the hypoglycaemic effect of A‐4166 was caused by a rapid‐onset and brief burst of insulin secretion. The pharmacokinetic profile of A‐4166 was consistent with the changes of the blood glucose and plasma insulin levels. Although the in vitro insulin‐releasing effect of A‐4166 was similar to that of sulphonylureas, its hypoglycaemic effect was more rapid and shorter‐lasting, associated with rapid absorption and clearance. Thus, A‐4166 may be useful in suppressing postprandial hyperglycaemia in patients with non‐insulin‐dependent diabetes mellitus.