Evolution of a New Class of Antihypertensive Drugs Targeting the Brain Renin-Angiotensin System

In addition to the circulating renin-angiotensin system, activation of the brain renin-angiotensin system plays an important role in the pathophysiology of hypertension. One of the major components of the brain renin-angiotensin system implicated in the development of hypertension is Ang III (angiotensin III). Brain Ang III, produced from Ang II (angiotensin II) by APA (aminopeptidase A), exerts a tonic stimulatory control over blood pressure in hypertensive rats. Targeting Ang III by inhibiting brain APA is now considered a potentially important target in the management of hypertension. This has led to development of RB150, an orally active prodrug of the specific and selective APA inhibitor, EC33. Orally administered RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain where it generates 2 active molecules of EC33 that block brain APA activity. This results in decreased brain Ang III formation and reduced blood pressure in hypertensive rats. The RB150-induced blood pressure decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances, and the improvement of the baroreflex function. RB150 was renamed firibastat by the World Health Organization. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well tolerated in healthy volunteers. Clinical efficacy of firibastat in hypertensive patients was, therefore, demonstrated in 2 phase II studies. Accordingly, firibastat could represent the first drug of a novel class of antihypertensive drugs targeting the brain renin-angiotensin system.