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., 4) 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 1H-1,2,3-triazoles as GPR88 agonists. Collectively, our medicinal chemistry efforts have resulted in a potent, efficacious, and brain-penetrant GPR88 agonist 53 (cAMP EC50 = 14 nM), which is a suitable probe to study GPR88 functions in the brain.
Evaluation of amide bioisosteres leading to 1,2,3-triazole containing compounds as GPR88 agonists
Design, synthesis, and structure-activity relationship studies
Rahman, M. T., Decker, A. M., Laudermilk, L., Maitra, R., Ma, W., Ben Hamida, S., Darcq, E., Kieffer, B. L., & Jin, C. (2021). Evaluation of amide bioisosteres leading to 1,2,3-triazole containing compounds as GPR88 agonists: Design, synthesis, and structure-activity relationship studies. Journal of Medicinal Chemistry, 64(16), 12397-12413. https://doi.org/10.1021/acs.jmedchem.1c01075, https://doi.org/10.1021/acs.jmedchem.1c01075