NI956/QGC006, a Potent Orally Active, Brain-Penetrating Aminopeptidase A Inhibitor for Treating Hypertension

Abstract

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We have shown that aminopeptidase A is involved in the formation of brain angiotensin III, which exerts tonic stimulatory control over blood pressure in hypertensive deoxycorticosterone acetate-salt rats and spontaneously hypertensive rats. We have also shown that injection of the specific and selective aminopeptidase A inhibitor, (3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid (EC33), by central route or its prodrug, RB150/firibastat, by oral route inhibited brain aminopeptidase A activity and blocked the formation of brain angiotensin III, normalizing blood pressure in hypertensive rats. These findings identified brain aminopeptidase A as a potential new therapeutic target for hypertension. We report here the development of a new aminopeptidase A inhibitor prodrug, NI956/QGC006, obtained by the disulfide bridge-mediated dimerization of NI929. NI929 is 10× more efficient than EC33 at inhibiting recombinant mouse aminopeptidase A activity in vitro. After oral administration at a dose of 4 mg/kg in conscious deoxycorticosterone acetate-salt rats, NI956/QGC006 normalized brain aminopeptidase A activity and induced a marked decrease in blood pressure of −44±13 mm Hg 4 hours after treatment ( P< 0.001), sustained over 10 hours (−21±12 mm Hg; P< 0.05). Moreover, NI956/QGC006 decreased plasma arginine-vasopressin levels, and increased diuresis and natriuresis, that may participate to the blood pressure decrease. Finally, NI956/QGC006 did not affect plasma sodium and potassium concentrations. This study shows that NI956/QGC006 is a best-in-class central-acting aminopeptidase A inhibitor prodrug. Our results support the development of hypertension treatments targeting brain aminopeptidase A.

Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies

“…The findings of Ferdinand et al support the strategy of using brain APA inhibitors to lower BP in subjects with resistant hypertension [ 94 ]. NI956/QGC006 is a new centrally acting APA inhibitor that is more effective than EC33 in lowering BP [ 95 ]. Extensive preclinical and clinical trials show the efficacy and safety of APA inhibitors, resulting in a sustained decrease in BP via downregulation of systemic AVP release and sympathetic activity and improvement in the baroreflex function of hypertensive animal models (Tables 1 and 2 ).…”

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

“…Firibastat is the first oral medication that may target the brain RAS with promising clinical application. Current efforts in designing new brainpenetrating APA inhibitors led to a 10-fold more potent new prodrug, NI956/QGC006, which has been shown to exert powerful antihypertensive effects in rats treated with DOCA-salt [106].…”

Nuevas perspectivas en el manejo de la hipertensión

“…Un nuevo inhibidor de la APA, NI956/ QGC006, ha sido utilizado en ratas, demostrando significativos descensos de presión arterial y de arginina vasopresina, con aumento de diuresis y natriuresis, sin afectar niveles plasmáticos de sodio y potasio 38 .…”