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. Epub 2021 Aug 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzeneacetamides / chemical synthesis
  • Benzeneacetamides / pharmacokinetics
  • Benzeneacetamides / pharmacology*
  • Blood-Brain Barrier / metabolism
  • Corpus Striatum / metabolism
  • Drug Design
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / deficiency
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*

Substances

  • Benzeneacetamides
  • Gpr88 protein, mouse
  • Oxadiazoles
  • Receptors, G-Protein-Coupled
  • Triazoles