Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166).
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.
Ikenoue
T
T
Life Science Laboratories, Ajinomoto Co., Inc., Yokohama, Japan.
Akiyoshi
M
M
Fujitani
S
S
Okazaki
K
K
Kondo
N
N
Maki
T
T
D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D004232:Diuretics; D004285:Dogs; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D013268:Stimulation, Chemical
D001786:Blood Glucose; D003510:Cyclohexanes; D004232:Diuretics; D007004:Hypoglycemic Agents; D007328:Insulin; D049993:Sodium Chloride Symporter Inhibitors; D000077715:Nateglinide; D010649:Phenylalanine; D003981:Diazoxide; D005905:Glyburide; D002118:Calcium