Discovery of 3,9-diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists with sleep-promoting activity in the rat

In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model. Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists pro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-07, Vol.20 (14), p.4201-4205
Hauptverfasser:	Coleman, Paul J., Schreier, John D., Roecker, Anthony J., Mercer, Swati P., McGaughey, Georgia B., Cox, Christopher D., Hartman, George D., Harrell, C. Meacham, Reiss, Duane R., Doran, Scott M., Garson, Susan L., Anderson, Wayne B., Tang, Cuyue, Prueksaritanont, Thomayant, Winrow, Christopher J., Renger, John J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alkanes - chemistry Alkanes - pharmacokinetics Alkanes - pharmacology Animals Aza Compounds - chemistry Aza Compounds - pharmacokinetics Aza Compounds - pharmacology Biological Availability Brain penetration Bridged Bicyclo Compounds - chemistry Bridged Bicyclo Compounds - pharmacokinetics Bridged Bicyclo Compounds - pharmacology Diazepane Drug Discovery Electroencephalography GPCR antagonist Hypnotics and Sedatives - chemistry Hypnotics and Sedatives - pharmacokinetics Hypnotics and Sedatives - pharmacology Insomnia Orexin Orexin Receptors Rats Rats, Sprague-Dawley Receptor Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, Neuropeptide - antagonists & inhibitors Sleep
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Zusammenfassung:	In this Letter, we describe the synthesis of constrained diazepanes including 3,9-diazabicyclo[4.2.1]nonane 8a that has improved oral bioavailability and sleep-promoting activity in a rat EEG model. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.05.047