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

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

  • J Med Chem. 2021 Aug 26;64(16):12397-12413. doi: 10.1021/acs.jmedchem.1c01075.
Md Toufiqur Rahman 1,  Ann M Decker 1,  Lucas Laudermilk 1,  Rangan Maitra 1,  Weiya Ma 2,  Sami Ben Hamida 2 3,  Emmanuel Darcq 2 3,  Brigitte L Kieffer 2 3,  Chunyang Jin 1
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
  • 2 Douglas Research Center, Department of Psychiatry, McGill University, Montréal, Quebec H4H 1R3, Canada.
  • 3 INSERM U1114, University of Strasbourg, Strasbourg 67085, France.
PMID: 34387471 DOI: 10.1021/acs.jmedchem.1c01075
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., 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.

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