Discovery of novel pyrrolopyridazine scaffolds as transient receptor potential vanilloid (TRPV1) antagonists

Bioorg Med Chem Lett. 2012 Nov 15;22(22):6888-95. doi: 10.1016/j.bmcl.2012.09.059. Epub 2012 Sep 25.

Abstract

A novel indolizine class of compounds was identified as TRPV1 antagonist from an HTS campaign. However, this indolizine class proved to be unstable and reacted readily with glutathione when exposed to light and oxygen. Reactivity was reduced by the introduction of a nitrogen atom alpha to the indolizine nitrogen. The pyrrolopyridazine core obtained proved to be inert to the action of light and oxygen. The synthesis route followed the one used for the indolizine compounds, and the potency and ADMET profile proved to be similar.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Drug Evaluation, Preclinical
  • Humans
  • Indolizidines / chemistry
  • Microsomes, Liver / metabolism
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism

Substances

  • Indolizidines
  • Pyridazines
  • Pyrroles
  • Pyrrolopyridazine
  • TRPV Cation Channels
  • TRPV1 protein, human