The neuropeptides orexin-A and orexin-B are derived from a common precursor peptide exclusively produced by perifornical and lateral hypothalamic neurons. These neurons project widely to key areas of the brain involved in the control of sleep-wake states, regulation of food intake, reward, addictive behaviours, panic, and anxiety. The orexin neuropeptides mediate their effect by stimulating two distinct G-protein coupled receptors, termed orexin-1 (OX1R) and orexin-2 (OX2R), that are co-located or selectively located in specific brain regions which suggest differentiated roles. For example, the OX2Rs are exclusively expressed in the tuberomammillary nuclei which are known to play a critical role in wake promotion. In agreement with this, the ability of OX2R antagonists to promote sleep is now well established and has led to a marketed dual OX1/OX2 receptor antagonist (DORA) Belsomera® (Suvorexant). Alternatively, Janssen and others have shown that the selective OX2R antagonist (SORA2) Seltorexant, is also effective at promoting sleep. These findings, are consistent with pre-clinical studies indicating that antagonism of the OX2 receptor is required to induce sleep, however, administration of a selective OX1 receptor antagonist has no effect. In addition to the ventral tegmental area, which is thought to mediate addictive behaviours, the 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. Presented here will be the structure, discovery, and first in human data of the selective OX1R antagonist JNJ-61393215, which was predicted and shown to provide targeted Ctrough levels for 24hr coverage after a QD dose. Furthermore, the presentation will highlight strategies to optimize OX1R selectivity and pharmacokinetics by taking advantage of the kinetic isotope effect. These efforts culminated in the discovery of JNJ-61393215, which has improved brain penetration and safety margins relative to our first SORA1 candidate, JNJ-54717793.

Discovery of JNJ-61393215: Selective orexin-1 receptor antagonist

2019 Fall National Meeting

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