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

Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype leading to MK-8133. [Display omitted] 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.