title: 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.affiliation: Department of Chemical Research-CV & CNS, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. shu-wei.yang@spcorp.com
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Yang
authors.forename: Ginny
authors.initials: G
authors.lastname: Ho
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: John
authors.initials: J
authors.lastname: Anthes
authors.forename: Xiomara
authors.initials: X
authors.lastname: Fernandez
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: John A
authors.initials: JA
authors.lastname: Hey
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D003371:Cough / Q000188:drug therapy*; D004285:Dogs; D055808:Drug Discovery; D006168:Guinea Pigs; D006801:Humans; D000077297:Pregnane X Receptor; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D000071230:Transcriptional Regulator ERG; D014326:Tropanes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014828:Vocalization, Animal / Q000187:drug effects; D000094942:Nociceptin Receptor
chemical_list: C543823:8-(bis(2-chlorophenyl)methyl)-3-(2-pyridinyl)-8-azabicyclo(3.2.1)octane; D000996:Antitussive Agents; C072312:ERG protein, human; D000077297:Pregnane X Receptor; D011725:Pyridines; D011957:Receptors, Opioid; D011987:Receptors, Steroid; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014326:Tropanes; D000094942:Nociceptin Receptor