Nicholas Carruthers

Discovery of selective Orexin-2 antagonists for the treatment of Primary Insomnia

Orexins (OX), also known as hypocretins, are the common names given to a pair of excitatory neuropeptides called OX-A and OX-B (also termed hypocretin-1 and hypocretin-2) derived from the common precursor prepro-OX that are exclusively produced by hypothalamic neurons.  OX-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.  As such, orexin receptor antagonists have been pursued by numerous laboratories as potential sleep promoting agents and several groups have demonstrated that blockade of the orexin-1 and orexin-2 receptors by dual OX1R/OX2R antagonists promotes sleep both in rats and in humans.  Our research efforts have focused on the discovery of selective OX2R antagonists, selective OX1R antagonists, and the characterization of the sleep promoting effects of selective blockade of either the orexin-2 receptor or the orexin-1 receptor.  Pre-clinical studies have shown that selective orexin-2 receptor antagonists are effective sleep promoting agents, indicating that selective antagonism of the orexin-2 receptor is sufficient to promote sleep.  Additional studies have shown that an orexin-1 receptor antagonist, when dosed alone, has no significant effect on sleep parameters in rat and in fact can attenuate the sleep promoting effects of a selective orexin-2 antagonist when dosed together with an orexin-2 antagonist.  These data led us to develop selective orexin-2 receptor antagonists as sleep promoting agents.  Towards that end, we now present the medicinal chemistry efforts and the pre-clinical characterization of a series of novel selective orexin-2 receptor antagonists that led to the discovery of JNJ-42847922 along with human pharmacokinetic data and safety data from Phase 1 clinical trials in healthy volunteers.