The orexin G protein-coupled receptors, OX1 and OX2, are neuropeptide receptors activated by the ligands orexin-A and orexin-B. The orexin system is highly conserved across mammalian species and is implicated in a range of functions with a common theme of arousal, including energy homeostasis, feeding, control of reward and sleep-wake regulation. Antagonists with diverse selectivity profiles have been identified over the past two decades, with the dual orexin antagonist suvorexant approved in 2014 for the treatment of insomnia. More recently there has been a focus on selective OX1 antagonists for the treatment of addictive disorders. Despite the amount of effort invested in this target family over the years, many chemical series have ultimately not been progressed into the clinic, with common issues being high clearance / poor PK properties and unacceptable physicochemical / developability properties. Sosei Heptares has a core platform called the StaR® technology that facilitates generation of optimised membrane protein samples for use in biophysical and structure-determination techniques. We have been pursuing structure-based drug discovery (SBDD) approaches for the discovery of orexin receptor modulators for a number of years. Within this body of work we have identified a fascinating diversity of ligand binding modes within the orthosteric sites of the OX1 and OX2 receptors, by ligand-receptor X-ray co-crystallisation of numerous in-house and literature chemotypes. Aspects of the structural insights and how we have leveraged these in pursuit of our dual and OX1 selective antagonists will be presented. In our OX1 selective program we have identified and progressed a number of chemical series, targeting an agent for cocaine addiction. The development of one such series, culminating in discovery of the lead compound HTL0027772 will be described. The chemical structure and properties of this optimised agent will be disclosed for the first time.

Discovery of selective OX1 antagonist HTL0027772 by structure-based drug design

2019 Fall National Meeting

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