[Orally active brain aminopeptidase A inhibitors on heart failure after myocardial infarction: Their development up to phase II clinical trials].

Abstract

The pathophysiology of heart failure after myocardial infarction involves, as arterial hypertension, hyperactivity of the brain renin-angiotensin system and sympathetic overactivation. Among the main effector peptides of the brain renin-angiotensin system, angiotensin II (AngII) and angiotensin III (AngIII) similarly activate type 1 angiotensin receptors, thereby increasing blood pressure and inducing cardiac dysfunction after myocardial infarction. Since AngII is converted in vivo into AngIII, the nature of the effector peptide remained to be clarified. We identified the enzymes involved in the metabolism of brain angiotensins and developed specific and selective inhibitors. These studies revealed the key role of brain AngIII in blood pressure regulation and cardiac function, highlighting brain aminopeptidase A, the enzyme responsible for brain AngIII formation, as a potential therapeutic target for treating arterial hypertension and myocardial infarction-induced heart failure. This led to the development of two, orally active, centrally acting, aminopeptidase A inhibitors, firibastat and QGC606, which were tested in various experimental models of arterial hypertension and heart failure, and demonstrated therapeutic potentialities up to phase 2 clinical trials in patients after myocardial infarction.