Clozel J P, Fischli W
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Arzneimittelforschung. 1993 Feb;43(2A):260-2.
Angiotensin converting enzyme (ACE) inhibitors are used for the treatment of hypertension and congestive heart failure. However, ACE not only cleaves angiotensin I but is also responsible for the degradation of bradykinin. Therefore, renin inhibitors which block the system at an early step without influence on bradykinin should be devoid of side effects. Since renin has a very strong species specificity, it was necessary to develop new techniques to measure arterial pressure as well as hypertension models in primates in order to select orally active renin inhibitors. Remikiren (Ro 42-5892, CAS 126371-83-3) is a very potent renin inhibitor in vitro (IC50 for human renin = 0.7 nmol/l) and in vivo. Despite short lasting biochemical changes the arterial blood pressure decrease induced by remikiren is very long lasting (over 24 h). Several in vivo experiments have shown that remikiren is specific for renin and does not decrease arterial pressure by an unrelated mechanism. In sodium depleted monkeys, the blood pressure decrease induced by remikiren was similar to the blood pressure decrease induced by cilazapril, an ACE inhibitor. Clinical results seem to confirm the preclinical findings and show that remikiren is indeed a potent orally active renin inhibitor inducing a long lasting blood pressure decrease.
血管紧张素转换酶（ACE）抑制剂用于治疗高血压和充血性心力衰竭。然而，ACE不仅能裂解血管紧张素I，还负责缓激肽的降解。因此，在早期阶段阻断该系统且不影响缓激肽的肾素抑制剂应该没有副作用。由于肾素具有很强的种属特异性，有必要开发新的技术来测量灵长类动物的动脉血压以及高血压模型，以便筛选口服活性肾素抑制剂。瑞米吉仑（Ro 42 - 5892，CAS 126371 - 83 - 3）在体外（对人肾素的IC50 = 0.7 nmol/l）和体内都是一种非常有效的肾素抑制剂。尽管生化变化持续时间较短，但瑞米吉仑引起的动脉血压下降却非常持久（超过24小时）。多项体内实验表明，瑞米吉仑对肾素具有特异性，不会通过无关机制降低动脉血压。在缺钠的猴子中，瑞米吉仑引起的血压下降与ACE抑制剂西拉普利引起的血压下降相似。临床结果似乎证实了临床前研究结果，表明瑞米吉仑确实是一种有效的口服活性肾素抑制剂，能引起持久的血压下降。
