Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists. Issue 6 (15th March 2017)

• Record Type: Journal Article
• Authors: Skudlarek, Jason W.; DiMarco, Christina N.; Babaoglu, Kerim; Roecker, Anthony J.; Bruno, Joseph G.; Pausch, Mark A.; O'Brien, Julie A.; Cabalu, Tamara D.; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L.; Wuelfing, W. Peter; Garson, Susan L.; Fox, Steven V.; Savitz, Alan T.; Harrell, Charles M.; Gotter, Anthony L.; Winrow, Christopher J.; Renger, John J.; Kuduk, Scott D.; Coleman, Paul J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 6(2017)
• Page Start: 1364
• Page End: 1370
• Publication Date: 2017-03-15
• Subjects: Orexin -- Insomnia -- GPCR -- Antagonist -- Sleep; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.02.012
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2 R subtype and culminating in the discovery of23, a highly potent, OX2 R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1 R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.