High ligand efficiency quinazoline compounds as novel A 2A adenosine receptor antagonists.

Autor: Bolteau R; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Duroux R; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Laversin A; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Vreulz B; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Shiriaeva A; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Stauch B; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern Califorinia, Los Angeles, CA, USA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Han GW; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern Califorinia, Los Angeles, CA, USA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Cherezov V; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern Califorinia, Los Angeles, CA, USA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Renault N; Univ. Lille, Inserm, U995 - LIRIC - Lille Inflammation Research International Center, ICPAL, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France., Barczyk A; Univ. Lille, Inserm, U995 - LIRIC - Lille Inflammation Research International Center, ICPAL, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France., Ravez S; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Coevoet M; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Melnyk P; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France., Liberelle M; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France. Electronic address: maxime.liberelle@univ-lille.fr., Yous S; Univ. Lille, Inserm, CHU Lille, U1172, LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Nov 05; Vol. 241, pp. 114620. Date of Electronic Publication: 2022 Jul 22.
DOI: 10.1016/j.ejmech.2022.114620
Abstrakt: The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A 2A receptor (A 2A AR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A 2A AR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A 2A AR antagonists. Among them, one compound showed a high affinity towards A 2A AR (21a, K i  = 20 nM). We crystallized this ligand in complex with A 2A AR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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