Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure-Activity Relationship Studies.

TitleEvaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure-Activity Relationship Studies.
Publication TypeJournal Article
Year of Publication2021
AuthorsRahman MToufiqur, Decker AM, Laudermilk L, Maitra R, Ma W, Ben Hamida S, Darcq E, Kieffer BL, Jin C
JournalJ Med Chem
Volume64
Issue16
Pagination12397-12413
Date Published2021 08 26
ISSN1520-4804
KeywordsAnimals, Benzeneacetamides, Blood-Brain Barrier, Corpus Striatum, Drug Design, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Structure, Oxadiazoles, Receptors, G-Protein-Coupled, Structure-Activity Relationship, Triazoles
Abstract

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.

DOI10.1021/acs.jmedchem.1c01075
Alternate JournalJ Med Chem
PubMed ID34387471
PubMed Central IDPMC8395584
Grant ListR01 AA026820 / AA / NIAAA NIH HHS / United States
R03 AA029013 / AA / NIAAA NIH HHS / United States