Identification of small molecule orexin agonists

ABSTRACT The goal of this project is to identify novel small molecule orexin agonists via high-throughput screening (HTS) of our in-house library of ~100k compounds. The orexin system consists of G protein-coupled receptors (GPCRs), OX1R and OX2R, and their endogenous neuropeptides, orexin-A and B, and plays a critical role in multiple functions including sleep and cognition. Orexin deficiency causes narcolepsy, a sleep disorder affecting 3 million people worldwide, and is also found in aging, Alzheimer’s and Parkinson’s diseases, conditions with disrupted sleep and cognitive impairment. Importantly, central administration of orexin-A reverses the narcoleptic symptoms in animal models of narcolepsy. Similarly, our team found that ROXA-43 and ROXA-47, the first small molecule dual orexin agonists developed by our team with low nanomolar potency and full efficacy at both OX1R and OX2R, promotes wakefulness, reduces sleep, and enhances memory in mice, without producing conditioned place preference (CPP). These findings support orexin agonism as a potential intervention for narcolepsy and many other conditions with orexin deficiency. However, the neuropeptides orexin-A and B have been the primary tools for orexin receptor activation, which are not suitable for systemic administration. Several small molecule orexin agonists, which are mostly OX2R selective, have been recently disclosed, but no orexin agonist drugs have advanced to the clinics. The most advanced candidate TAK-994 demonstrated statistically significant improvement in daytime wakefulness in phase II clinical trials but has been discontinued for hepatotoxicity concerns. The dual orexin agonists developed by our team have high molecular weight, poor brain permeability and low solubility, highlighting the need for novel orexin agonists. In this application, we propose to identify novel orexin agonists, particularly for OX2R, which plays a more prominent role in narcolepsy, by HTS of our in-house compound library and to evaluate their biological activities and preliminary ADME properties. Discovery of orexin agonists may provide basis for the development of orexin agonist-based pharmacotherapies for many neurological disorders associated with orexin deficiency that currently do not have effective treatments.