Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat.
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
Coleman
Paul J
PJ
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, United States. paul_coleman@merck.com
Schreier
John D
JD
Roecker
Anthony J
AJ
Mercer
Swati P
SP
McGaughey
Georgia B
GB
Cox
Christopher D
CD
Hartman
George D
GD
Harrell
C Meacham
CM
Reiss
Duane R
DR
Doran
Scott M
SM
Garson
Susan L
SL
Anderson
Wayne B
WB
Tang
Cuyue
C
Prueksaritanont
Thomayant
T
Winrow
Christopher J
CJ
Renger
John J
JJ
D000473:Alkanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055808:Drug Discovery; D004569:Electroencephalography; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
D000473:Alkanes; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D006993:Hypnotics and Sedatives; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C017573:nonane