首页> 外文OA文献 >Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (−)-N-(trans-4-isopropylcyclohexane-carbonyl)-D-phenylalanine (A-4166)
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Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (−)-N-(trans-4-isopropylcyclohexane-carbonyl)-D-phenylalanine (A-4166)

机译:新型口服降糖药(-)-N-(反式-4-异丙基环己烷-羰基)-D-苯丙氨酸(A-4166)的降血糖和促胰岛素作用

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摘要

(−)-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 3×10-6 M to 3×10-4 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.A-4166 displaced [3H]-glibenclamide bound to intact HIT-T15 cells in a concentration-dependent manner. The Ki value was 4.34±0.04×10−7 M, 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.
机译:新型口服降血糖药(-)-N-(反式-4-异丙基环己烷羰基)-D-苯丙氨酸(A-4166)是一种非磺酰脲类胰岛素促分泌剂,我们研究了A-4166的胰岛素释放作用和降血糖作用在体外和体内,A-4166刺激了大鼠新鲜分离的胰岛中胰岛素的分泌,其浓度为2.8μmM葡萄糖,浓度为3×10-6 M至3×10-4M。 A-4166和格列本脲的促胰岛素作用之间对葡萄糖的依赖性无明显差异,两种药物之间均未观察到累加或协同作用。A-4166取代的[3H]-格列本脲与完整的HIT-T15细胞结合以浓度依赖的方式。 Ki值为4.34±0.04×10−7 M,A-4166的置换潜能在格列本脲和甲苯磺丁酰胺之间,与格列齐特相似。在禁食比格犬中,A-4166表现出剂量依赖性降血糖口服后1至10 mg kg-1的效果。与磺酰脲类药物相比,A-4166的降血糖作用更早发生,持续时间更短。同时测量血浆胰岛素水平显示,A-4166的降血糖作用是由胰岛素分泌的快速发作和短暂爆发引起的。 A-4166的药代动力学特征与血糖和血浆胰岛素水平的变化是一致的。尽管A-4166的体外胰岛素释放作用与磺脲类药物相似,但其降血糖作用更快,持续时间更短,与快速吸收和清除有关。因此,A-4166可用于抑制非胰岛素依赖型糖尿病患者的餐后高血糖。

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