Shibasaki M, Asano M, Fukunaga Y, Usui T, Ichihara M, Murakami Y, Nakano K, Fujikura T
Medicinal Research Laboratories II, Yamanouchi Pharmaceutical Co., Ltd., Japan.
Am J Hypertens. 1991 Dec;4(12 Pt 1):932-8. doi: 10.1093/ajh/4.12.932.
A novel renin inhibitor, YM-21095 [2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L- histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-but anol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100 micrograms/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.
一种新型肾素抑制剂YM-21095（[2RS），（3S）-3-[Nα-[1,4-二氧代-4-吗啉代-2-(1-萘基甲基)-丁基]-L-组氨酰氨基]-4-环己基-1-[(1-甲基-5-四氮唑基)硫代]-2-丁醇）已在我们实验室合成。本研究的目的是在体外和体内实验中评估YM-21095的药理特性。YM-21095抑制人肾素的IC50值为4.7×10(-10)mol/L。YM-21095也是松鼠猴肾素的有效抑制剂，但对狗、兔和大鼠的肾素抑制效果较差。YM-21095对肾素的作用具有高度特异性，因为在浓度高达10(-4)mol/L时，它不抑制组织蛋白酶D、胃蛋白酶或血管紧张素转换酶。YM-21095对酶（胃蛋白酶、胰凝乳蛋白酶、胰蛋白酶）和松鼠猴组织匀浆（肝脏、肾脏、小肠）的蛋白水解作用具有抗性。静脉输注YM-21095（0.1至100微克/千克/分钟）可降低麻醉的缺钠和钠充足松鼠猴的平均血压，并以剂量依赖方式抑制血浆肾素活性，对心率无影响。YM-21095对缺钠松鼠猴的降压作用约为钠充足松鼠猴的10倍。给清醒的缺钠松鼠猴口服YM-21095可使收缩压产生剂量相关的降低。我们得出结论，YM-21095是灵长类肾素的有效且高度特异性抑制剂，并具有降血压作用。
