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|
|Date Published||2021 08 26|
|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|
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.
|Alternate Journal||J Med Chem|
|PubMed Central ID||PMC8395584|
|Grant List||R01 AA026820 / AA / NIAAA NIH HHS / United States |
R03 AA029013 / AA / NIAAA NIH HHS / United States