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Central-acting aminopeptidase a inhibitors for new treatment of hypertension: from discovery to clinical trial.
Authors : C Llorens-Cortes (Paris,FR), Y Marc (Paris,FR), R Hmazzou (Paris,FR), M Keck (Paris,FR), A Flahault (Paris,FR), BP Roques (Paris,FR), F Balavoine (Paris,FR), M Azizi (Paris,FR)
C. Llorens-Cortes1
,
Y. Marc2
,
R. Hmazzou1
,
M. Keck2
,
A. Flahault1
,
B.P. Roques3
,
F. Balavoine4
,
M. Azizi5
,
1INSERM U 1050, College de France - Paris - France
,
2National Institute of Health and Medical Research (INSERM home), U1050, Quantum Genomics - Paris - France
,
3University Paris-Descartes - Paris - France
,
4Quantum Genomics - Paris - France
,
5European Hospital Georges Pompidou, Clinical Investigation Center - Paris - France
,
On behalf: Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Paris, France
The hyperactivity of the brain renin–angiotensin system (RAS) has been implicated in the development and maintenance of arterial hypertension (HTA).
Our aim was to demonstrate that normalizing brain RAS hyperactivity could constitute a new therapeutic approach for HTA treatment
We first demonstrated in the brain that aminopeptidase A (APA) is the enzyme generating angiotensin III (AngIII) from AngII. Then, using the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), we showed that AngIII is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in hypertensive rats. This suggests that brain APA may be a potential therapeutic target for HTA treatment. We then designed RB150 {4,4-dithio[bis(3-aminobutyl sulfonic acid)]}, an orally active prodrug of EC33. RB150, given orally in conscious deoxycorticosterone acetate-salt (DOCA-salt) rats or spontaneously hypertensive rats, crosses the intestinal, hepatic and blood-brain barriers, enters the brain, where it is cleaved by brain reductases, generating two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and induce a marked and sustained decrease in BP. The RB150-induced BP decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances and the improvement of the baroreflex function (Figure below). RB150 was renamed firibastat by OMS. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well-tolerated in healthy volunteers.
Firibastat could constitute the first drug candidate of a new class of antihypertensive agents targeting the brain RAS, the clinical efficacy of which (Phase IIa and Phase IIb) in hypertensive patients was achieved.
