Mathilde Keck1,2, Reda Hmazzou1, Catherine Llorens-Cortes3. 1. Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR 7241, 11 Place Marcelin Berthelot, 75005, Paris, France. 2. Quantum Genomics, 33 rue Marbeuf, 75008, Paris, France. 3. Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR 7241, 11 Place Marcelin Berthelot, 75005, Paris, France. c.llorens-cortes@college-de-france.fr.
Abstract
PURPOSE OF REVIEW: To review the data supporting the use of aminopeptidase A (APA) inhibitor prodrugs as centrally acting antihypertensive agents. RECENT FINDINGS: Brain renin-angiotensin system (RAS) hyperactivity has been implicated in the development and maintenance of hypertension. Angiotensin III, generated by APA, one of the main effector peptides of the brain RAS, exerts a tonic stimulatory control over blood pressure in hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, leading to the development of RB150/firibastat, an orally active prodrug of the specific and selective APA inhibitor, EC33. When given orally, RB150/firibastat crosses the gastrointestinal and blood-brain barriers, enters the brain, and generates two active molecules of EC33 which inhibit brain APA activity, blocking brain angiotensin III formation, and decrease blood pressure for several hours in hypertensive rats. Orally active APA inhibitor prodrugs, by blocking brain RAS activity, represent promising novel strategy for treating hypertension.
PURPOSE OF REVIEW: To review the data supporting the use of aminopeptidase A (APA) inhibitor prodrugs as centrally acting antihypertensive agents. RECENT FINDINGS: Brain renin-angiotensin system (RAS) hyperactivity has been implicated in the development and maintenance of hypertension. Angiotensin III, generated by APA, one of the main effector peptides of the brain RAS, exerts a tonic stimulatory control over blood pressure in hypertensiverats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, leading to the development of RB150/firibastat, an orally active prodrug of the specific and selective APA inhibitor, EC33. When given orally, RB150/firibastat crosses the gastrointestinal and blood-brain barriers, enters the brain, and generates two active molecules of EC33 which inhibit brain APA activity, blocking brain angiotensin III formation, and decrease blood pressure for several hours in hypertensiverats. Orally active APA inhibitor prodrugs, by blocking brain RAS activity, represent promising novel strategy for treating hypertension.
Entities:
Keywords:
Aminopeptidase A inhibitor; Brain renin–angiotensin system; Hypertension
Authors: John W Wright; Elizabeth Tamura-Myers; Wendy L Wilson; Bernard P Roques; Catherine Llorens-Cortes; Robert C Speth; Joseph W Harding Journal: Am J Physiol Regul Integr Comp Physiol Date: 2002-11-14 Impact factor: 3.619
Authors: A Reaux; M C Fournie-Zaluski; C David; S Zini; B P Roques; P Corvol; C Llorens-Cortes Journal: Proc Natl Acad Sci U S A Date: 1999-11-09 Impact factor: 11.205
Authors: A Réaux; N de Mota; S Zini; S Cadel; M C Fournié-Zaluski; B P Roques; P Corvol; C Llorens-Cortès Journal: Neuroendocrinology Date: 1999-05 Impact factor: 4.914
Authors: Marie-Claude Fournie-Zaluski; Celine Fassot; Bruno Valentin; Dragan Djordjijevic; Annabelle Reaux-Le Goazigo; Pierre Corvol; Bernard P Roques; Catherine Llorens-Cortes Journal: Proc Natl Acad Sci U S A Date: 2004-05-10 Impact factor: 11.205
Authors: Sara Abdulrahman Alomar; Sarah Ali Alghabban; Hadeel Abdulaziz Alharbi; Mehad Fahad Almoqati; Yazid Alduraibi; Ahmed Abu-Zaid Journal: Avicenna J Med Date: 2021-01-05