Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, Institut National de la Santé et de la Recherche Médicale U1050, Paris, France; Quantum Genomics, Paris, France.
Quantum Genomics, Paris, France.
Can J Cardiol. 2020 May;36(5):721-731. doi: 10.1016/j.cjca.2020.03.005. Epub 2020 Mar 6.
The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI.
心力衰竭（HF）和高血压的病理生理学被认为涉及脑肾素-血管紧张素系统（RAS）的活性亢进。血管紧张素 III 是脑 RAS 中的关键效应肽，为高血压大鼠的血压提供了紧张性刺激控制。血管紧张素肽酶 A（APA）是生成脑血管紧张素 III 的酶，是高血压治疗的潜在治疗靶点。我们在这里重点介绍 RB150/firibastat 的研究，这是特异性和选择性 APA 抑制剂 EC33 的第一个前药，能够穿过血脑屏障。我们考虑从治疗靶点发现到前药的临床试验来研究它的发展。口服给药后，firibastat 穿过胃肠道和血脑屏障。到达大脑后，它被裂解生成 EC33，抑制脑 APA 活性，降低各种高血压实验模型中的血压。在健康人类受试者中进行的 I 期试验中，firibastat 表现出良好的临床和生物学耐受性，即使在高剂量下也是如此。然后在来自不同种族的高血压患者的 II 期试验中显示出有效降低血压的作用。脑 RAS 活性亢进导致过度的交感神经活动，这可能导致心肌梗死后心力衰竭（HF）。口服 firibastat（心肌梗死后 4 或 8 周）的慢性治疗已被证明可使小鼠脑 APA 活性正常化。这种作用伴随着脑 RAS 和交感神经活动的正常化，减少心脏纤维化和肥大，并预防心脏功能障碍。因此，firibastat 可能代表高血压患者临床管理的一种新的治疗进展，并可能在心肌梗死后 HF 患者中具有治疗前景。
