Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists

Bioorg Med Chem. 2018 Jan 1;26(1):295-307. doi: 10.1016/j.bmc.2017.11.051. Epub 2017 Dec 2.

Abstract

A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood-brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.

Keywords: ADMET model; CB(1) antagonism; Diarylpyridazines; Docking studies; Sulfenamides; Sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfamerazine / chemical synthesis
  • Sulfamerazine / chemistry
  • Sulfamerazine / pharmacology*
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Ligands
  • Pyridazines
  • Receptor, Cannabinoid, CB1
  • Sulfonamides
  • sulfenamide
  • Sulfamerazine