QGC606: A Best-in-Class Orally Active Centrally Acting Aminopeptidase A Inhibitor Prodrug for Treating Heart Failure Following Myocardial Infarction

Can J Cardiol. 2022 Jun;38(6):815-827. doi: 10.1016/j.cjca.2022.01.019. Epub 2022 Jan 26.

Abstract

Background: Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI.

Methods: Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control.

Results: Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice.

Conclusions: Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibrosis
  • Glutamyl Aminopeptidase
  • Heart Failure* / drug therapy
  • Heart Failure* / etiology
  • Humans
  • Male
  • Mice
  • Myocardial Infarction* / complications
  • Myocardial Infarction* / drug therapy
  • Myocardium / pathology
  • Prodrugs* / therapeutic use
  • RNA, Messenger
  • Ramipril / pharmacology
  • Ramipril / therapeutic use
  • Ventricular Remodeling

Substances

  • Prodrugs
  • RNA, Messenger
  • Glutamyl Aminopeptidase
  • Ramipril