Kühnle H F, Wolff H P, Schmidt F H, Reiter R
Boehringer Mannheim GmbH, Dept. Medical Research, Mannheim, Federal Republic of Germany.
Biochem Pharmacol. 1990 Oct 15;40(8):1821-5. doi: 10.1016/0006-2952(90)90362-o.
A single oral or intraperitoneal application of 2-(3-phenylpropoxyimido)-butyrate (BM 13.677) resulted in a dose-dependent blood-glucose-lowering effect in fasted guinea-pigs. The threshold dose and the EC50 were estimated as 25 mg/kg and 63 mg/kg, respectively, which is between that of the biguanides phenformin and metformin. A rise in blood lactate concentrations was observed only at high doses of BM 13.677, but was not related to an irreversible metabolic inhibition. Among several rodent species studied the potency of the drug decreased in the order guinea-pig much greater than mouse greater than rat = rabbit. Inhibition of hepatic gluconeogenesis by the drug was demonstrated in the perfused liver or hepatocytes of guinea-pigs. Inhibition of glucose production by the perfused liver in the presence of 0.1 mM BM 13.677 was dependent on the substrate and decreased in the order: lactate greater than pyruvate greater than alanine much greater than propionate greater than glycerol = fructose. This suggests a specific interaction of the drug with a mitochondrial key reaction of gluconeogenesis. Stimulation of glucose oxidation in rat diaphragm by the compound (EC50 = 0.85 mM) suggests that besides inhibition of gluconeogenesis also extrahepatic effects contribute to the blood-glucose-lowering effects of the drug.
单次口服或腹腔注射2-(3-苯丙氧基亚氨基)-丁酸酯（BM 13.677）可使禁食的豚鼠血糖呈剂量依赖性降低。阈剂量和半数有效浓度（EC50）分别估计为25毫克/千克和63毫克/千克，介于双胍类药物苯乙双胍和二甲双胍之间。仅在高剂量的BM 13.677时观察到血乳酸浓度升高，但这与不可逆的代谢抑制无关。在所研究的几种啮齿动物中，该药物的效力按以下顺序降低：豚鼠＞小鼠＞大鼠 = 兔子。在豚鼠的灌注肝脏或肝细胞中证实了该药物对肝糖异生的抑制作用。在存在0.1 mM BM 13.677的情况下，灌注肝脏对葡萄糖生成的抑制作用取决于底物，其降低顺序为：乳酸＞丙酮酸＞丙氨酸＞丙酸＞甘油 = 果糖。这表明该药物与糖异生的线粒体关键反应存在特异性相互作用。该化合物对大鼠膈肌葡萄糖氧化的刺激作用（EC50 = 0.85 mM）表明，除了抑制糖异生外，肝外作用也有助于该药物降低血糖的作用。
