2. Academic Validation
  3. Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

  • J Med Chem. 2020 Mar 12;63(5):2074-2094. doi: 10.1021/acs.jmedchem.9b00584.
Germain Homerin 1 2,  Samir Jawhara 1,  Xavier Dezitter 1 3,  Davy Baudelet 1 2,  Pierrick Dufrénoy 1 2,  Benoît Rigo 1 2,  Régis Millet 1 3,  Christophe Furman 1 3,  Guillaume Ragé 1 3,  Emmanuelle Lipka 1 4,  Amaury Farce 1 3,  Nicolas Renault 1 3,  Boualem Sendid 1,  Rogatien Charlet 1,  Jordan Leroy 1,  Mélodie Phanithavong 5,  Camille Richeval 5,  Jean-François Wiart 5,  Delphine Allorge 5,  Sahil Adriouch 6 7,  Valérie Vouret-Craviari 8 9,  Alina Ghinet 1 2 10
Affiliations

Affiliations

  • 1 CHRU de Lille, Faculté de Médecine-Pôle Recherche, Inserm U995, LIRIC, Université de Lille, Place Verdun, F-59045 Lille Cedex, France.
  • 2 Yncréa Hauts-de-France, UCLille, Laboratoire de Pharmacochimie, Hautes Etudes d'Ingénieur (HEI), 13 rue de Toul, F-59046 Lille, France.
  • 3 Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114, 3 rue du Pr Laguesse, F-59006 Lille, France.
  • 4 Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, F-59006 Lille Cedex, France.
  • 5 Laboratoire de Toxicologie & Génopathies, CHRU de Lille, Centre de Biologie Pathologie, Blvd du Pr. J. Leclercq, CS 70001, F-59037 Lille, France.
  • 6 INSERM U905, F-76183 Rouen, France.
  • 7 Institute for Research and Innovation in Biomedicine, Normandie University, F-76183 Rouen, France.
  • 8 Institute for Research on Cancer and Aging (IRCAN), F-06100 Nice, France.
  • 9 University of Nice Cote d'Azur (UCA), F-06100 Nice, France.
  • 10 Faculty of Chemistry, "Al. I. Cuza" University of Iasi, Blvd Carol I, nr. 11, 700506 Iasi, Romania.
PMID: 31525963 DOI: 10.1021/acs.jmedchem.9b00584
Abstract

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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