Firibastat, the first-in-class brain aminopeptidase a inhibitor, in the management of hypertension: a review of clinical trials

Abstract An unfortunate subset of hypertensive patients develops resistant hypertension in which optimal doses of three or more first-line antihypertensive drugs fail to sufficiently control blood pressure. Patients with resistant hypertension represent a high-risk and difficult-to-treat group, and such patients are at amplified jeopardies for substantial hypertension-related multi-organ failure, morbidity, and mortality. Thus, there is a pressing requirement to better improve blood pressure control through the pharmaceutical generation of novel classes of antihypertensive drugs that act on newer and alternative therapeutic targets. The hyperactivity of the brain renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of hypertension in various experimental and genetic hypertensive animal models. In the brain, angiotensin-II is metabolized to angiotensin-III by aminopeptidase A (APA), a membrane-bound zinc metalloprotease enzyme. A large body of evidence has previously established that angiotensin-III is one of the main effector peptides of the brain RAS. Angiotensin-III exerts central stimulatory regulation over blood pressure through several proposed mechanisms. Accumulating evidence from preclinical studies demonstrated that the centrally acting APA inhibitor prodrugs (firibastat and NI956) are very safe and effective at reducing blood pressure in various hypertensive animal models. The primary purpose of this study is to narratively review the published phase I–II literature on the safety and efficacy of APA inhibitors in the management of patients with hypertension. Moreover, a summary of ongoing clinical trials and future perspectives are presented.