Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

Creators: Homerin, Germain; Jawhara, Samir; Dezitter, Xavier; Baudelet, Davy; Dufrénoy, Pierrick; Rigo, Benoit; Millet, Régis; Furman, Christophe; Ragé, Guillaume; Lipka, Emmanuelle; Farce, Amaury; Renault, Nicolas; Sendid, Boualem; Charlet, Rogatien; Leroy, Jordan; Phanithavong, Mélodie; Richeval, Camille; Wiart, Jean-François; Allorge, Delphine; Adriouch, Sahil; Vouret-Craviari, Valérie; Ghinet, Alina

Others:: Lille Inflammation Research International Center - U 995 (LIRIC) ; Institut Pasteur de Lille ; Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille); Laboratoire de pharmacochimie [Lille] ; Université catholique de Lille (UCL)-Hautes Etudes d'Ingénieur [Lille] (HEI) ; Université catholique de Lille (UCL); Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL) ; Université de Lille, Droit et Santé; Laboratoire de Chimie Analytique (EA 4034) ; Université de Lille, Droit et Santé; Toxicologie et Génopathies [CHRU Lille] ; Pôle de Biologie Pathologie Génétique [CHU Lille] ; Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille); Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes ; Université de Rouen Normandie (UNIROUEN) ; Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM); Institute for Research and Innovation in Biomedicine (IRIB) ; Université de Rouen Normandie (UNIROUEN) ; Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institut de Recherche sur le Cancer et le Vieillissement (IRCAN) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA); Alexandru Ioan Cuza University of Iași [Romania]; We gratefully acknowledge the "Métropole Européenne de Lille" (MEL) for G.H.'s Ph.D. scholarship, the DigestScience Foundation (Foundation on Digestive Tract Diseases and Nutrition), and the Institut National du Cancer, France (INCa, project P2X7 2015–137) for financial support.; We also acknowledge the National Cancer Institute (NCI) for biological evaluation of compounds on their 60-cell panel: the testing was performed by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (the URL to the Program's website: http://dtp.cancer.gov). We thank Thierry Juhel (IRCAN) for assistance with animals. We thank Nathalie Jouy and Emilie Floquet of the BICeL Facility for access to systems and technical advices in flow cytometry.

Description

This report deals with the design, the synthesis, and the pharmacological evaluation of pyroglutamide-based P2X7 antagonists. A dozen were shown to possess improved properties, among which inhibition of YO-PRO-1/TO-PRO-3 uptake and IL1β release upon BzATP activation of the receptor and dampening signs of DSS-induced colitis on mice, in comparison with reference antagonist GSK1370319A. Docking study and biological evaluation of synthesized compounds has highlighted new SAR, and low toxicity profiles of pyroglutamides herein described are clues for the finding of a usable h-P2X7 antagonist drug. Such a drug would raise the hope for a cure to many P2X7-dependent pathologies, including inflammatory, neurological, and immune diseases.

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Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

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