Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an n,n-disubstituted-1,4-diazepane scaffold that promotes sleep in rats.
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, WP14-2, West Point, PA 19486, USA. david_whitman@merck.com
David B
DB
Whitman
Christopher D
CD
Cox
Michael J
MJ
Breslin
Karen M
KM
Brashear
John D
JD
Schreier
Michael J
MJ
Bogusky
Rodney A
RA
Bednar
Wei
W
Lemaire
Joseph G
JG
Bruno
George D
GD
Hartman
Duane R
DR
Reiss
C Meacham
CM
Harrell
Richard L
RL
Kraus
Yuxing
Y
Li
Susan L
SL
Garson
Scott M
SM
Doran
Thomayant
T
Prueksaritanont
Chunze
C
Li
Christopher J
CJ
Winrow
Kenneth S
KS
Koblan
John J
JJ
Renger
Paul J
PJ
Coleman
D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects; D064446:Orexin Receptors; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D001381:Azepines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide