Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.
Can J Physiol Pharmacol. 2022 Jul 1;100(7):573-583. doi: 10.1139/cjpp-2022-0010. Epub 2022 Apr 3.
Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10%-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs, this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is an investigational, novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research that underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension that cannot be well controlled with classical antihypertensive drugs.
内皮素已成为治疗全身性高血压的一个靶点。作为一种血管收缩剂、促有丝分裂剂、连接脉冲压和血管重塑的物质，以及醛固酮和儿茶酚胺释放的介质，内皮素是高血压和靶器官损伤的关键因素。在 10%-20%的高血压人群中，高血压对不同类别的降压药物联合治疗具有耐药性。由于内皮素不受当前降压药物的作用，这可能表明这种耐药性至少部分是由于对内皮素的依赖。这一假设得到了以下观察结果的支持：这种形式的高血压通常对盐敏感，并且盐刺激内皮素系统。此外，内皮素系统在易患耐药性高血压的人群中被激活，如非裔美国人或肥胖或阻塞性睡眠呼吸暂停患者。阿普西坦是一种正在研究中的新型强效双重内皮素受体拮抗剂（ERA），目前处于治疗难治性高血压的 3 期开发阶段。本文讨论了支持发现这种 ERA 的研究以及选择其首个临床适应证的研究，该适应证适用于不能用经典降压药物很好控制的高血压形式的患者。
