Abstract
The pathophysiology of heart failure (HF) and hypertension are thought to involve
brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector
peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP)
in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating
brain angiotensin III, constitutes a potential therapeutic target for hypertension
treatment. We focus here on studies of RB150/firibastat, the first prodrug of the
specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We
consider its development from therapeutic target discovery to clinical trials of the
prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain
barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits
brain APA activity, lowering BP in various experimental models of hypertension. Firibastat
was clinically and biologically well tolerated, even at high doses, in phase I trials
conducted in healthy human subjects. It was then shown to decrease BP effectively
in patients of various ethnic origins with hypertension in phase II trials. Brain
RAS hyperactivity leads to excessive sympathetic activity, which can contribute to
HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or
8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect
is accompanied by a normalization of brain RAS and sympathetic activities, reducing
cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may
therefore represent a novel therapeutic advance in the clinical management of patients
with hypertension and potentially with HF after MI.
Résumé
La physiopathologie de l'insuffisance cardiaque (IC) et de l'hypertension artérielle
impliquerait une hyperactivité du système rénine-angiotensine (SRA) cérébral. L'angiotensine
III, un peptide effecteur clé du SRA cérébral, exerce un effet stimulateur tonique
de la pression artérielle (PA) chez les rats hypertendus. L'aminopeptidase A (APA),
l'enzyme responsable de la production d'angiotensine III dans le cerveau, constitue
une cible thérapeutique potentielle pour le traitement de l'hypertension. Nous nous
concentrons ici sur les études du RB150/firibastat, le premier promédicament de l’EC33,
inhibiteur spécifique et sélectif de l'APA, capable de traverser la barrière hémato-encéphalique
après administration par voie orale. Nous présentons son développement depuis la découverte
de la cible thérapeutique jusqu'aux essais cliniques du promédicament. Après administration
orale, le firibastat traverse les barrières gastro-intestinale et hémato-encéphalique.
À son arrivée dans le cerveau, il est clivé pour générer l'EC33 qui inhibe l'activité
de l'APA dans le cerveau, faisant baisser la PA dans divers modèles expérimentaux
d'hypertension. Le firibastat est cliniquement et biologiquement bien toléré, même
à fortes doses, dans des essais de phase I menés sur des sujets sains. Il a ensuite
été démontré qu'il réduisait efficacement la PA chez des patients de diverses origines
ethniques souffrant d'hypertension, lors d'essais de phase II. L'hyperactivité du
SRA cérébral entraîne une activité sympathique excessive, qui peut contribuer à l’IC
après un infarctus du myocarde (IM). Il a été démontré qu'un traitement chronique
de firibastat par voie orale (4 ou 8 semaines après l'IM) normalise l'activité cérébrale
de l'APA chez la souris. Cet effet s'accompagne d'une normalisation de l'activité
cérébrale du SRA et de l’activité sympathique, réduisant la fibrose et l'hypertrophie
cardiaques et prévenant la dysfonction cardiaque. Le firibastat pourrait donc représenter
une nouvelle avancée thérapeutique dans la prise en charge clinique des patients souffrant
d'hypertension et potentiellement d’IC après un IM.
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Article info
Publication history
Published online: March 06, 2020
Accepted:
March 2,
2020
Received:
January 31,
2020
Footnotes
See page 728 for disclosure information.
Identification
Copyright
© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
