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

• Published in: Bioorganic & medicinal chemistry letters 2010-07, Vol.20 (14), p.4201-4205
• Main Authors: 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: Article
• Language: English
• Subjects: 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.047

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.