Discovery of Orally Active 3-Pyridinyl-tropane As a Potent Nociceptin Receptor Agonist for the Management of Cough

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 caps...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-09, Vol.52 (17), p.5323-5329
Hauptverfasser:	Yang, Shu-Wei, Ho, Ginny, Tulshian, Deen, Greenlee, William J, Anthes, John, Fernandez, Xiomara, McLeod, Robbie L, Hey, John A, Xu, Xiaoying
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antitussive Agents - administration & dosage Antitussive Agents - chemistry Antitussive Agents - pharmacology Antitussive Agents - therapeutic use Biological and medical sciences Cough - drug therapy Dogs Drug Discovery Guinea Pigs Humans Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments 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
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Beschreibung
Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9008218