Kokubu T, Hiwada K, Murakami E, Muneta S, Morisawa Y, Yabe Y, Koike H, Iijima Y
2nd Department of Internal Medicine, Ehime University School of Medicine, Japan.
J Cardiovasc Pharmacol. 1987;10 Suppl 7:S88-90. doi: 10.1097/00005344-198706107-00014.
Dipeptide and tripeptide derivatives containing a statine residue were synthesized as human renin inhibitors. ES-305, bis[(1-naphthyl)methyl]acetyl-histidyl-statine-2(S)-methylbutylami de, was found to be a highly potent human renin inhibitor that is species-specific and enzyme-specific. The replacement of the methylbutylamide of ES-305 with the leucyl-lysinol (ES-1005) showed similar high potency against human renin (Ki value of 2.4 x 10(-9) M) and monkey renin (Ki value of 7.9 x 10(-9) M) as ES-305. ES-1005 competitively inhibited human renin. The compound was about one order of magnitude less potent against pig, dog, and rabbit renins. It had moderate inhibitory potencies against cathepsin D and pepsin (IC50 of cathepsin D and pepsin of 1.6 x 10(-5) and 8.0 x 10(-6) M, respectively). ES-1005, a newly synthesized tripeptide derivative containing statine, is a highly potent inhibitor of not only primate renin but also a wide variety of nonprimate renins.
合成了含有沙他汀残基的二肽和三肽衍生物作为人肾素抑制剂。ES - 305，双[(1 - 萘基)甲基]乙酰基 - 组氨酰 - 沙他汀 - 2(S) - 甲基丁酰胺，被发现是一种高效的人肾素抑制剂，具有物种特异性和酶特异性。用亮氨酰 - 赖氨酸醇（ES - 1005）取代ES - 305的甲基丁酰胺后，对人肾素（Ki值为2.4×10(-9) M）和猴肾素（Ki值为7.9×10(-9) M）显示出与ES - 305相似的高效力。ES - 1005竞争性抑制人肾素。该化合物对猪、狗和兔肾素的效力约低一个数量级。它对组织蛋白酶D和胃蛋白酶具有中等抑制效力（组织蛋白酶D和胃蛋白酶的IC50分别为1.6×10(-5) M和8.0×10(-6) M）。ES - 1005是一种新合成的含沙他汀的三肽衍生物，不仅是灵长类肾素的高效抑制剂，也是多种非灵长类肾素的高效抑制剂。
