Brain aminopeptidase A inhibitors and cardiovascular regulations – CARDOBAPAI

Hypertension (HTN) remains still difficult to control: In France, only 50% of the hypertensive population is at the blood pressure (BP) target, more than 25% of the hypertensive patients more than 3 antihypertensive treatments and 10% of the hypertensive patients are resistant to at least 3 antihypertensive drugs (including a diuretic). Consequently, there is a need to develop new classes of antihypertensive agents acting on new targets with different mechanisms of action to improve blood pressure (BP) control and the associated cardiovascular risks. Evidences support that hyperactivity of the brain renin-angiotensin system (RAS) participates to the development and maintenance of HTN. Research programs carried out by the laboratory of Dr. C. Llorens-Cortes have allowed to demonstrate in hypertensive rats, that in the brain RAS, angiotensin III (AngIII) is one of the main effector peptides exerting a tonic stimulatory action on the control of BP. Thanks to a collaboration with the laboratory of Pr. BP. Roques, the first specific and selective aminopeptidase A (APA) inhibitor was developed, the EC33. This inhibitor has allowed to demonstrate the key role of APA, in the formation of brain AngIII from AngII. Thus, blockade of brain APA activity by these compounds normalizes BP in hypertensive rats. This highlights that brain APA constitutes a novel potential therapeutic target for the treatment of HTN. For a clinical use of this inhibitors it was necessary to administrate them by oral route, with this goal a prodrug of the EC33, the RB150 as well as the NI956 were developed. The RB150 administrated by oral route cross the intestinal, hepatic and blood brain barriers, enter in the brain, it is deprotected and generate EC33 which block the brain APA activity, inhibit the brain AngIII formation and decrease BP in a dose dependant maneer during several hours in two experimental models of HTN. Since 2007, the Quantum Genomics Company has exclusive license on the patent taken on these molecules and their derivatives. Thanks to the support of the ANR (BiotecS gathering the laboratory of Dr. C. Llorens-Cortes and Quantum Genomics Company), the preclinical development of the RB150/QGC001 as well as the first clinical trial (Phase 1) has been done.
The laboratory of Dr. C. Llorens-Cortes and Quantum Genomics Company would like to create a “Laboratoire commun” and their work will be base on five axes:
1- Study the mecanism of action of APA inhibitor (RB150) especially the consequences on the other metabolics pathways on the brain renin-angiotensin system.
2- Sutdy the synergy of action of APA inhibitor (RB150) with blockers of the systemic renin-angiotensin system
3- Characterize the pharmacological properties of NI956 (APA inhibitor with a Ki of 30 nM, 10 times better than that of EC33
4- Identify and developp new APA inhibitors potent and sélective with pharmacokinetic and pharmacodynamic properties compatible with the development of new antihypertensive drugs.
5- Search and validate a new therapeutic application for APA inhibitor especially for heart Failure
In conclusion the aim of the creation of this laboratory is to perform transversal research from molecules discovery to clinical trials. The laboratory allow in a same place to join molecular modelers, medicinal chemists, molecular biologists and pharmacologists. In addition the laboratory will pursue his collaboration with Clinical Investigation Center of the European Georges Pompidou Hospital, directed by Pr. M. Azizi