CP - 71,362：一种对犬肾素酶具有选择性的五肽肾素抑制剂。

CP-71,362: a pentapeptide renin inhibitor selective for the canine enzyme.

作者信息

Mangiapane M L, MacAndrew J T, Ellery S S, Smith A H, Purcell I M, Kleinman E F, Holt W F, Murphy W R

机构信息

Department of Cardiovascular and Metabolic Diseases, Pfizer Central Research, Groton, CT 06340.

出版信息

Clin Exp Hypertens. 1994 Jul;16(4):507-33. doi: 10.3109/10641969409067959.

DOI:10.3109/10641969409067959

PMID:7920458

Abstract

Most renin inhibitors are primate-specific. In the present paper, we describe the effects of CP-71,362, a pentapeptide which preferentially inhibits canine (and to a lesser extent, rat) plasma renin. Vs. the canine enzyme, its affinity (IC50 = 3.3 x 10(-12) M) is 1000x greater than for rat renin (IC50 = 3.3 x 10(-9) M), and 1000x greater than for human (IC50 = 2.3 x 10(-8) M), cynomolgus monkey (IC50 = 1.6 x 10(-8) M), or guinea pig (IC50 = 5.2 x 10(-8) M) enzyme. In anesthetized, sodium-depleted dogs, intravenous infusion of CP-71,362 (ED50 = 1.1 micrograms/kg/min) resulted in dose-dependent decreases (up to -35 mm Hg) in mean arterial pressure (MAP). The maximum fall in MAP was equivalent to that produced by i.v. captopril (5 mg/kg). Similar falls in MAP were observed in conscious sodium-depleted SHR (ED50 = 5 micrograms/kg/min). Via bolus injection, the action of CP-71,362 was relatively brief in dog, guinea pig, and SHR. We conclude that CP-71,362 is a potent canine/rat renin inhibitor and causes profound MAP lowering in these species.

摘要

大多数肾素抑制剂具有灵长类特异性。在本文中，我们描述了五肽CP - 71,362的作用，它优先抑制犬（在较小程度上也抑制大鼠）血浆肾素。与犬肾素酶相比，其亲和力（IC50 = 3.3×10⁻¹² M）比对大鼠肾素（IC50 = 3.3×10⁻⁹ M）高1000倍，比对人（IC50 = 2.3×10⁻⁸ M）、食蟹猴（IC50 = 1.6×10⁻⁸ M）或豚鼠（IC50 = 5.2×10⁻⁸ M）肾素酶高1000倍。在麻醉的、缺钠的犬中，静脉输注CP - 71,362（ED50 = 1.1微克/千克/分钟）导致平均动脉压（MAP）呈剂量依赖性下降（最大下降至 - 35毫米汞柱）。MAP的最大降幅与静脉注射卡托普利（5毫克/千克）所产生的降幅相当。在清醒的缺钠自发性高血压大鼠（SHR）中也观察到类似的MAP下降（ED50 = 5微克/千克/分钟）。通过推注给药，CP - 71,362在犬、豚鼠和SHR中的作用相对短暂。我们得出结论，CP - 71,362是一种有效的犬/大鼠肾素抑制剂，可使这些物种的MAP显著降低。