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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Blood Pressure / physiology
  • Brain / metabolism*
  • Disease Models, Animal
  • Disulfides / pharmacology*
  • Glutamyl Aminopeptidase / antagonists & inhibitors*
  • Hypertension / drug therapy*
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Male
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Renin-Angiotensin System / drug effects
  • Sulfonic Acids / pharmacology*

Substances

  • Disulfides
  • EC 33
  • RB 150
  • Sulfonic Acids
  • Glutamyl Aminopeptidase