Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

Germain Homerin (1, 2) , Samir Jawhara (1) , Xavier Dezitter (1, 3) , Davy Baudelet (1, 2) , Pierrick Dufrénoy (1, 2) , Benoit Rigo (1, 2) , Régis Millet (3, 1) , 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) , Alina Ghinet (1, 2, 9)

1 LIRIC - Lille Inflammation Research International Center - U 995
2 Laboratoire de pharmacochimie [Lille]
3 ICPAL - Institut de Chimie Pharmaceutique Albert Lespagnol
4 EA 4034 - Laboratoire de Chimie Analytique
5 Toxicologie et Génopathies [CHRU Lille]
6 Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes
7 IRIB - Institute for Research and Innovation in Biomedicine
8 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
9 Alexandru Ioan Cuza University of Iași [Romania]

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.

Domains: Chemical Sciences; Immunology; Biochemistry, Molecular Biology

Germain Homerin, Samir Jawhara, Xavier Dezitter, Davy Baudelet, Pierrick Dufrénoy, et al.. Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease. Journal of Medicinal Chemistry, 2019, Women in Medicinal Chemistry, Epub ahead of print, ⟨10.1021/acs.jmedchem.9b00584⟩. ⟨hal-02376260⟩