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. British Journal of Pharmacology (1997) 120, 177–186; doi:10.1038/sj.bjp.0700875