CGP 38560：口服活性、低分子量、高效且特异性强的肾素抑制剂。

CGP 38 560: orally active, low-molecular-weight renin inhibitor with high potency and specificity.

作者信息

Wood J M, Criscione L, de Gasparo M, Bühlmayer P, Rüeger H, Stanton J L, Jupp R A, Kay J

机构信息

Research Department, Ciba-Geigy, Basel, Switzerland.

出版信息

J Cardiovasc Pharmacol. 1989 Aug;14(2):221-6.

PMID:2476594

Abstract

CGP 38 560 is a low-molecular-weight (730) inhibitor of human renin that contains only one natural amino acid. In vitro, it is a potent inhibitor of human renin (Ki with tetradecapeptide, 0.4 X 10(-9) M). It has a high enzyme specificity (Ki values against human pepsin, gastricsin, and cathepsin D are 5 X 10(-6), 3 X 10(-6), and 0.6 X 10(-6) M) and is also species specific (IC50 values against human, marmoset, dog, and rat plasma renins are 7 X 10(-10), 7 X 10(-10), 7 X 10(-9), and 1 X 10(-6) M). In vivo, CGP 38 560 inhibits plasma renin activity (PRA) and lowers blood pressure (BP) after oral administration to conscious, normotensive, furosemide-pretreated marmosets. A dose of 10 mg/kg induces complete inhibition of PRA and a decrease in BP of 23 +/- 3 mm Hg (n = 4) after 30 min. These effects persist for up to 2 h. Blockade of the renin-angiotensin system appears to cause the hypotensive response since it is completely prevented by pretreatment with a converting-enzyme inhibitor. These findings demonstrate that the molecular size of renin inhibitors may be reduced to improve their oral activity without loss of potency or specificity.

摘要

CGP 38560是一种低分子量（730）的人肾素抑制剂，仅含一种天然氨基酸。在体外，它是一种有效的人肾素抑制剂（与十四肽的Ki为0.4×10⁻⁹ M）。它具有高酶特异性（对人胃蛋白酶、胃泌素和组织蛋白酶D的Ki值分别为5×10⁻⁶、3×10⁻⁶和0.6×10⁻⁶ M），并且也是种属特异性的（对人、狨猴、狗和大鼠血浆肾素的IC50值分别为7×10⁻¹⁰、7×10⁻¹⁰、7×10⁻⁹和1×10⁻⁶ M）。在体内，给清醒、血压正常、经速尿预处理的狨猴口服CGP 38560后，它能抑制血浆肾素活性（PRA）并降低血压（BP）。剂量为10 mg/kg时，30分钟后可完全抑制PRA，血压下降23±3 mmHg（n = 4）。这些作用可持续长达2小时。肾素 - 血管紧张素系统的阻断似乎导致了降压反应，因为用转化酶抑制剂预处理可完全预防这种反应。这些发现表明，肾素抑制剂的分子大小可以减小以提高其口服活性，而不会丧失效力或特异性。