The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety.
The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
Ho
Ginny D
GD
Department of Chemical Research, CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Anthes
John
J
Bercovici
Ana
A
Caldwell
John P
JP
Cheng
Kuo-Chi
KC
Cui
Xiaoming
X
Fawzi
Ahmad
A
Fernandez
Xiomara
X
Greenlee
William J
WJ
Hey
John
J
Korfmacher
Walter
W
Lu
Sherry X
SX
McLeod
Robbie L
RL
Ng
Fay
F
Torhan
April Smith
AS
Tan
Zheng
Z
Tulshian
Deen
D
Varty
Geoffrey B
GB
Xu
Xiaoying
X
Zhang
Hongtao
H