Format

Send to

Choose Destination
Hypertension. 2019 Jun;73(6):1300-1307. doi: 10.1161/HYPERTENSIONAHA.118.12499.

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

Author information

1
From the Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR 7241, Paris (M.K., H.D.A., D.C., A.F., C.L.-C.).
2
Quantum Genomics, Tour Montparnasse, Paris, France (M.K., D.C., F.B.).
3
USR 3278 CRIOBE, PSL Research University, EPHEUPVD-CNRS, Université de Perpignan Via Domitia, Laboratoire d'Excellence, France (N.I.).
4
U1022 INSERM/UMR 8258 CNRS, Université Paris-Descartes (Paris V), France (B.R.).

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.

KEYWORDS:

aminopeptidase A; angiotensin III; blood pressure; brain; hypertension; natriuresis; prodrugs; renin-angiotensin system

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center