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

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.

• Authors: Shu-Wei Yang, Ginny Ho, Deen Tulshian, William J Greenlee, John Anthes, Xiomara Fernandez, Robbie L McLeod, John A Hey, Xiaoying Xu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 17 Pg. 5323-9 (Sep 10 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19678644 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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