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.

• Authors: Mathilde Keck, Hugo De Almeida, Delphine Compère, Nicolas Inguimbert, Adrien Flahault, Fabrice Balavoine, Bernard Roques, Catherine Llorens-Cortes
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 73 Issue 6 Pg. 1300-1307 (06 2019) ISSN: 1524-4563 [Electronic] United States
• PMID: 31067198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Disulfides
• EC 33
• Sulfonic Acids
• firibastat
• Glutamyl Aminopeptidase

Topics

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