| Literature DB >> 31525963 |
Germain Homerin1,2, Samir Jawhara1, Xavier Dezitter1,3, Davy Baudelet1,2, Pierrick Dufrénoy1,2, Benoît Rigo1,2, Régis Millet1,3, Christophe Furman1,3, Guillaume Ragé1,3, Emmanuelle Lipka1,4, Amaury Farce1,3, Nicolas Renault1,3, Boualem Sendid1, Rogatien Charlet1, Jordan Leroy1, Mélodie Phanithavong5, Camille Richeval5, Jean-François Wiart5, Delphine Allorge5, Sahil Adriouch6,7, Valérie Vouret-Craviari8,9, Alina Ghinet1,2,10.
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.Entities:
Year: 2019 PMID： 31525963 DOI： 10.1021/acs.jmedchem.9b00584
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446