Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties.

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 OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

• Authors: Scott D Kuduk, Jason W Skudlarek, Christina N DiMarco, Joseph G Bruno, Mark H Pausch, Julie A O'Brien, Tamara D Cabalu, Joanne Stevens, Joseph Brunner, Pamela L Tannenbaum, Susan L Garson, Alan T Savitz, Charles M Harrell, Anthony L Gotter, Christopher J Winrow, John J Renger, Paul J Coleman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 12 Pg. 2488-92 (Jun 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 25981685 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• MK-6096
• MK-8133
• Orexin Receptor Antagonists
• Orexin Receptors
• Piperidines
• Pyrimidines
• Triazoles

Topics

• Animals
• Dogs
• Half-Life
• Mice
• Orexin Receptor Antagonists (chemistry, pharmacokinetics, therapeutic use)
• Orexin Receptors (chemistry, metabolism)
• Piperidines (chemistry, pharmacokinetics, therapeutic use)
• Protein Binding
• Pyrimidines (chemistry)
• Rats
• Sleep Initiation and Maintenance Disorders (drug therapy, veterinary)
• Structure-Activity Relationship
• Triazoles (chemistry, pharmacokinetics, therapeutic use)