1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists

Bioorg Med Chem. 2016 Apr 15;24(8):1619-36. doi: 10.1016/j.bmc.2016.02.031. Epub 2016 Feb 27.

Abstract

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.

Keywords: Addiction; Antagonist; DA D3 receptor; Dopamine; Neuroscience.

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • 1,2,4-triazolyl octahydropyrrolo(2,3-b)pyrrole
  • Ether-A-Go-Go Potassium Channels
  • Pyrroles
  • Receptors, Dopamine D3
  • Triazoles