Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166)

Br J Pharmacol. 1997 Jan;120(1):137-45. doi: 10.1038/sj.bjp.0700875.


1. (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166), a novel oral hypoglycaemic agent is a non-sulphonylurea insulin secretagogue. 2. We investigated the insulin-releasing action and hypoglycaemic effect of A-4166 compared to sulphonylureas in vitro and in vivo. 3. A-4166 stimulated insulin secretion from rat freshly isolated pancreatic islets at concentrations from 3 x 10(-6) M to 3 x 10(-4) M 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. 4. A-4166 displaced [3H]-glibenclamide bound to intact HIT-T15 cells in a concentration-dependent manner. The Ki value was 4.34 +/- 0.04 x 10(7) M, and the displacement potency of A-4166 was between that of glibenclamide and tolbutamide, being similar to that of gliclazide. 5. Inf 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. 6. 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. 7. The pharmacokinetic profile of A-4166 was consistent with the changes of the blood glucose and plasma insulin levels. 8. 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.

MeSH terms

  • Animals
  • Binding, Competitive
  • Blood Glucose / metabolism
  • Calcium / metabolism
  • Cell Line
  • Cyclohexanes / pharmacology*
  • Diazoxide / pharmacology
  • Diuretics
  • Dogs
  • Glyburide / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Nateglinide
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Rats
  • Rats, Wistar
  • Sodium Chloride Symporter Inhibitors / pharmacology
  • Stimulation, Chemical


  • Blood Glucose
  • Cyclohexanes
  • Diuretics
  • Hypoglycemic Agents
  • Insulin
  • Sodium Chloride Symporter Inhibitors
  • Nateglinide
  • Phenylalanine
  • Diazoxide
  • Glyburide
  • Calcium