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HOMERIN Germain (INSERM U995 éq. 07 - Alina GHINET)
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@mail :  g.homerin@yncrea.fr      tél. :  0686335353


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Titre de la communication :
Structure-activity relationships of new ligands of the P2X7 receptor for the development of drug-candidates with anti-inflammatory potential
Auteurs (et leurs adresses) de la communication :
Germain HOMERIN, Benoît RIGO, Xavier DEZITTER, Christophe FURMAN, Emmanuelle LIPKA, Régis MILLET and Alina GHINET* Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine – Pôle recherche, Place Verdun, F-59045 Lille Cedex, Fran
Résumé de la communication :
INTRODUCTION
The P2X7 receptor is a transmembrane ion channel belonging to the purinergic system. Its activation by ligands such as ATP leads to a K+ efflux and to a Ca2+ and Na+ influx within the cell. It is expressed all over the body, mostly on immune system cells.
This receptor has been studied for years for the implication in the inflammation process. It causes the maturation and release of proinflammatory cytokines such as IL-1β. Moreover, under repeated or prolonged activation, the P2X7R is able to form a membrane pore which leads frequently to apoptosis via different mechanisms. According to in vitro and in vivo studies, these characteristics could be used in the treatment of inflammation and cancers.
Inflammatory bowel diseases (IBDs) are crippling diseases and an estimated 200 000 people sufferer from them in France. Current therapies only focus on suppressing symptoms to give patients a better quality of life, but they do not cure them. However, the development of potential new treatments is on-going, in particular with the development of new antagonists of the P2X7 receptor. This receptor is responsible for interleukins release and so, takes part in the inflammatory process of IBD's patients. Lastly, even though the role in cancer is not well understood many arguments exist in favor of using P2X7R antagonists and exploiting them for their implication in cell death.

DESIGN
A previous study in our research team based on data from the literature (a) led to define a pharmacophore (model of the interactions needed to antagonize the receptor). We designed P2X7 receptor's ligands with potential antagonist activity, based on a pyroglutamic-like central connector.

RESULTS and DISCUSSION
To date, we have synthesized about a hundred compounds in 8 different series. Some antagonists have been identified with IC50 values in vitro in the nanomolar range and have allowed us to establish new SAR for the development of new series.(b) Our on-going studies, on the one hand, will focus on designing and synthesizing new ligands of the P2X7R based on new SAR; on the other hand, we will handle the problematic of distribution and metabolism of active antagonists we will have identified.
Moreover, recent data such as antifungal properties suggest that some of our best P2X7R antagonists may reduce Candida albicans (a fungus involved in IBDs) proliferation. These findings must be confirmed, but then we could think of medicines with synergistic effects: that would antagonize the cell's IL-1β processing and release; and at the same time diminish the LPS production by fungus.

Bibliographic references:
(a) Chambers, L.J. et al. WO 2008003697, Chem.Abstr., 2008, 148, 145026.
(b) Homerin, G. et al. ZrCl4 as a new catalyst for ester amidation: an efficient synthesis of h-P2X7R antagonists, Tetrahedron Lett., 2016, 57, 1165.)

HOMERIN Germain (INSERM U995 éq. 07 - Alina GHINET)