Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7)

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7135-41. doi: 10.1016/j.bmcl.2012.09.074. Epub 2012 Oct 2.

Abstract

Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure-activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders.

Publication types

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

MeSH terms

  • Drug Design*
  • Humans
  • Protein Binding
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship

Substances

  • 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one
  • NPBWR1 protein, human
  • Pyridazines
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Small Molecule Libraries
  • pyridazine