Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure-Activity Relationship Studies.
Title | Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure-Activity Relationship Studies. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Rahman MToufiqur, Decker AM, Laudermilk L, Maitra R, Ma W, Ben Hamida S, Darcq E, Kieffer BL, Jin C |
Journal | J Med Chem |
Volume | 64 |
Issue | 16 |
Pagination | 12397-12413 |
Date Published | 2021 08 26 |
ISSN | 1520-4804 |
Keywords | Animals, 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. |
DOI | 10.1021/acs.jmedchem.1c01075 |
Alternate Journal | J Med Chem |
PubMed ID | 34387471 |
PubMed Central ID | PMC8395584 |
Grant List | R01 AA026820 / AA / NIAAA NIH HHS / United States R03 AA029013 / AA / NIAAA NIH HHS / United States |