Scott Boyd B, McGeehan Gerard M, Harrison Richard K
Vitae Pharmaceuticals, Discovery Biology, 502 West Office Center Dr. Ft. Washington, PA 19034, USA.
Curr Protein Pept Sci. 2006 Jun;7(3):241-54. doi: 10.2174/138920306777452330.
Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAS) which controls blood pressure and volume. The biological function of renin is to cleave the N-terminus of angiotensinogen releasing the decapeptide, angiotensin I (ANGI). Subsequently, angiotensin I is further processed by the angiotensin converting enzyme (ACE) to produce angiotensin II (ANGII). The RAS cascade is a major target for the clinical management of hypertension. Current clinical treatments include angiotensin converting enzyme inhibitors (ACEi) and ANGII receptor blockers (ARBs). As the rate-limiting enzyme in ANGII production, renin inhibitors have been pursued as an additional class of anti-hypertensives. Clinical studies conducted with renin inhibitors have shown them to be as effective as ACE inhibitors in lowering blood pressure. Most importantly, inhibitors of renin may have a number of potential advantages over ACEi and ARBs. Renin is specific for angiotensinogen and will not carry the ancillary pharmacology associated with ACEi or ARBs. To date, no renin inhibitors have made it to market. The development of these inhibitors has been hindered by poor bioavailability and complex synthesis. However, despite the pharmacokinetic challenges of designing renin inhibitors, the enzyme remains a promising target for the development of novel treatments for hypertension. This review will consist of an overview of renin biology, the pharmacology of renin and RAS and focus in on renin as a target for blood pressure regulation. We also cover the evaluation of renin inhibitors in animal models and clinical studies. Presently a number of new generation inhibitors of renin are in development with at least one in the clinic and these will be discussed. Finally we will discuss what might distinguish renin inhibitors from current therapeutic options and discuss other therapeutic indications renin inhibitors might have.
肾素是肾素-血管紧张素-醛固酮系统（RAS）中的限速酶，该系统控制血压和血容量。肾素的生物学功能是切割血管紧张素原的N端，释放出十肽血管紧张素I（ANGI）。随后，血管紧张素I在血管紧张素转换酶（ACE）的作用下进一步加工生成血管紧张素II（ANGII）。RAS级联反应是高血压临床治疗的主要靶点。目前的临床治疗方法包括血管紧张素转换酶抑制剂（ACEi）和ANGII受体阻滞剂（ARBs）。作为ANGII生成中的限速酶，肾素抑制剂已被视为另一类抗高血压药物。使用肾素抑制剂进行的临床研究表明，它们在降低血压方面与ACE抑制剂同样有效。最重要的是，肾素抑制剂可能比ACEi和ARBs具有许多潜在优势。肾素对血管紧张素原具有特异性，不会带有与ACEi或ARBs相关的辅助药理学作用。迄今为止，尚无肾素抑制剂上市。这些抑制剂的开发受到生物利用度差和合成复杂的阻碍。然而，尽管设计肾素抑制剂存在药代动力学挑战，但该酶仍然是开发高血压新疗法的一个有前景的靶点。本综述将概述肾素生物学、肾素和RAS的药理学，并重点关注肾素作为血压调节靶点的情况。我们还将涵盖肾素抑制剂在动物模型和临床研究中的评估。目前有多种新一代肾素抑制剂正在研发中，至少有一种已进入临床，我们将对此进行讨论。最后，我们将讨论肾素抑制剂与当前治疗选择的区别，并探讨肾素抑制剂可能具有的其他治疗适应症。
