Orexin A & B (hypocretin 1 & 2) are two neuropeptides produced in discretely localized neurons in the hypothalamus with widespread projections to various brain regions. These peptides activate two G-protein coupled receptors Ox1 and Ox2, generally leading to excitatory postsynaptic effects. The orexin system plays a major role in the regulation of the sleep-wake cycle, feeding and reward seeking. It was therefore suggested that orexin receptor antagonists could be useful for the treatment of related disorders, in particular insomnia. Positive proof of concept clinical studies in primary insomnia were reported with four structurally divers dual orexin receptor antagonists (Almorexant, Suvorexant, SB-649868 and MK-6096).Here, we present the discovery, optimization and preclinical characterization of a novel class of orexin receptor antagonists that induce sleep in rodents. Interestingly, they exhibit a remarkably distinct effect on the sleep architecture determined by EEG when compared to previously reported clinical candidates.

Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture

244th National Meeting (2012)

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