Orexin receptors are G-protein coupled receptors expressed within regions of the brain that regulate wakefulness through downstream pathways involving histaminergic, dopaminergic, and cholinergic activation. Orexin receptors bind excitatory orexin neuropeptides which are secreted by neurons projecting from the lateral hypothalamus. Clinical and preclinical studies suggest orexin receptor antagonists could provide a novel therapy for treating insomnia and other disorders in which sleep/wake cycles are disrupted. The identification of potent orexin receptor antagonists is an active area of investigation, and small molecule antagonists have recently progressed through late stage clinical development. We have disclosed the discovery of dual orexin receptor antagonists (MK-4305,suvorexant; MK-6096, filorexant) and OX2R-selective antagonists (MK-1064).  This presentation will highlight those discoveries and describe the preclinical properties of dual and OX2R-selective antagonists.

Discovery and characterization of OX2R/OX1R and OX2R antagonists for the treatment of sleep disorders

248th National Meeting (2014)

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