Discovery of orally active 3-pyridinyl-tropane as a potent nociceptin receptor agonist for the management of cough

J Med Chem. 2009 Sep 10;52(17):5323-9. doi: 10.1021/jm9008218.

Abstract

A series of 3-pyridinyl-tropane analogues based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. From the SAR study and our lead optimization efforts, compound 10 was found to possess potent oral antitussive activity in the capsaicin-induced guinea pig model. The rationale for compound selection and the biological profile of the optimized lead (10) are disclosed.

MeSH terms

  • Administration, Oral
  • Animals
  • Antitussive Agents / administration & dosage
  • Antitussive Agents / chemistry*
  • Antitussive Agents / pharmacology*
  • Antitussive Agents / therapeutic use
  • Cough / drug therapy*
  • Dogs
  • Drug Discovery
  • Guinea Pigs
  • Humans
  • Nociceptin Receptor
  • Pregnane X Receptor
  • Pyridines / administration & dosage*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Rats
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Receptors, Steroid / antagonists & inhibitors
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors
  • Transcriptional Regulator ERG
  • Tropanes / administration & dosage*
  • Tropanes / chemistry
  • Tropanes / pharmacology*
  • Tropanes / therapeutic use
  • Vocalization, Animal / drug effects

Substances

  • 8-(bis(2-chlorophenyl)methyl)-3-(2-pyridinyl)-8-azabicyclo(3.2.1)octane
  • Antitussive Agents
  • ERG protein, human
  • Pregnane X Receptor
  • Pyridines
  • Receptors, Opioid
  • Receptors, Steroid
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Tropanes
  • Nociceptin Receptor