The neuropeptides orexin-A and orexin-B derives from a common precursor peptide exclusively produced by perifornical and lateral hypothalamic neurons orexin neuropeptides hypocretin-1 (OXA) and hypocretin-2 (OXB) originate in the hypothalamus. Orexin-producing neurons project widely to key areas of the brain and are predominantly involved in the control of wakefulness and also in the regulation of food intake, reward, addictive behaviors and stress. The OX neuropeptides mediate their effect by stimulating two distinct G-protein coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) that are co-located or selectively located in specific brain areas suggesting differentiated roles from a common precursor and have been shown to exert their mode of action on the Orexin-1 (OX1) or Orexin-2 receptors (OX2). These receptors are either co-expressed or selectively expressed in key areas of the central nervous system that mediate sleep-wake, addiction, reward, mood, panic, and anxiety. The selective expression of these receptors suggest differentiated roles within the CNS. For example, the OX2Rs are exclusively expressed in the tuberomammillary nuclei which play a critical role in wake promotion. In agreement with this, the ability of OX2R antagonists to promote sleep by inhibiting wake is now well established. This has led to a marketed dual OX1/OX2 receptor antagonist (DORA), Belsomera® (suvorexant). In line with pre-clinical studies indicating that antagonism of the OX2 receptor is required to induce sleep, but not the OX1 receptor, Janssen and others have reported that selective OX2R antagonists, are effective at promoting sleep in healthy human volunteers. In contrast to the OX2Rs, OX1Rs are selectively expressed in the bed nucleus of the stria terminalis, amygdala, cingulate cortex and locus coeruleus which play a role in panic and anxiety. In addition to the ventral tegmental area which is thought to mediate addictive behaviors. As researchers in academia and industry look to more clearly delineate the role and selectively target the OX1R in more complex emotional behavior (addiction, panic, anxiety) improved tool compounds are needed.<br/><br/>Presented here will be the discovery, synthetic methods and SAR associated with novel selective OX1R antagonists and their evaluation in selected preclinical models of panic, anxiety and addiction. In addition, we will highlight our first candidate for preclinical development.

Discovery of selective orexin-1 receptor antagonists

254th National Meeting (2017)

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