Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure-Activity Relationship Studies.
Fiche publication
Date publication
août 2021
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DARCQ Emmanuel
Tous les auteurs :
Rahman MT, Decker AM, Laudermilk L, Maitra R, Ma W, Ben Hamida S, Darcq E, Kieffer BL, Jin C
Lien Pubmed
Résumé
The orphan receptor GPR88 has been implicated in a number of striatal-associated disorders, yet its endogenous ligand has not been discovered. We have previously reported that the amine functionality in the 2-AMPP-derived GPR88 agonists can be replaced with an amide (e.g., ) without losing activity. Later, we have found that the amide can be replaced with a bioisosteric 1,3,4-oxadiazole with improved potency. Here, we report a further study of amide bioisosteric replacement with a variety of azoles containing three heteroatoms, followed by a focused structure-activity relationship study, leading to the discovery of a series of novel 1,4-disubstituted 1-1,2,3-triazoles as GPR88 agonists. Collectively, our medicinal chemistry efforts have resulted in a potent, efficacious, and brain-penetrant GPR88 agonist (cAMP EC = 14 nM), which is a suitable probe to study GPR88 functions in the brain.
Mots clés
Animals, Benzeneacetamides, chemical synthesis, Blood-Brain Barrier, metabolism, Corpus Striatum, metabolism, Drug Design, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Structure, Oxadiazoles, chemical synthesis, Receptors, G-Protein-Coupled, agonists, Structure-Activity Relationship, Triazoles, chemical synthesis
Référence
J Med Chem. 2021 08 26;64(16):12397-12413