SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists

Bioorg Med Chem Lett. 2013 Feb 1;23(3):614-9. doi: 10.1016/j.bmcl.2012.12.030. Epub 2012 Dec 20.

Abstract

In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure-activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC(50), and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.

Publication types

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

MeSH terms

  • Analgesics / pharmacology
  • Fluorenes / chemistry*
  • Fluorenes / pharmacology
  • Inhibitory Concentration 50
  • Molecular Structure
  • Peptides / pharmacology
  • Protein Binding / drug effects
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one
  • 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one
  • Analgesics
  • Fluorenes
  • NPBWR1 protein, human
  • Peptides
  • Pyridazines
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide