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 capsaicin-induced guinea pig model. The rationale for compound selection and the biological profile of the optimized lead (10) are disclosed.
Yang
Shu-Wei
SW
Department of Chemical Research-CV & CNS, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. shu-wei.yang@spcorp.com
Ho
Ginny
G
Tulshian
Deen
D
Greenlee
William J
WJ
Anthes
John
J
Fernandez
Xiomara
X
McLeod
Robbie L
RL
Hey
John A
JA
Xu
Xiaoying
X
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
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