Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties. Issue 12 (15th June 2015)

• Record Type: Journal Article
• Authors: Kuduk, Scott D.; Skudlarek, Jason W.; DiMarco, Christina N.; Bruno, Joseph G.; Pausch, Mark H.; O'Brien, Julie A.; Cabalu, Tamara D.; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L.; Garson, Susan L.; Savitz, Alan T.; Harrell, Charles M.; Gotter, Anthony L.; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 12(2015)
• Page Start: 2488
• Page End: 2492
• Publication Date: 2015-06-15
• Subjects: Orexin -- Insomnia -- GPCR -- Antagonist -- Sleep; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.066
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2 R subtype leading to MK-8133. Abstract: Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2 R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to6b ; which was highly potent, OX2 R selective, and exhibited excellent development properties.