Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic propertiesElectronic supplementary information (ESI) available. See DOI: 10.1039/c5md00027k©Heptares Therapeutics 2015. The HEPTARES name is a trademark of Heptares Therapeutics Ltd

• Main Authors: Christopher, John A, Aves, Sarah J, Brown, Jason, Errey, James C, Klair, Suki S, Langmead, Christopher J, Mace, Oliver J, Mould, Richard, Patel, Jayesh C, Tehan, Benjamin G, Zhukov, Andrei, Marshall, Fiona H, Congreve, Miles
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c5md00027k

A novel series of potent, selective, and orally efficacious dual antagonists of the orexin receptors has been investigated, resulting in the identification of lead compound 27 (HTL6641). Comprehensive data for 27 are presented, including in vivo PK parameters, confirmation of receptor occupancy through ex vivo binding and efficacy in a rat sleep model. A key feature of the series is a short dissociation half-life, measured by surface plasmon resonance (SPR) using stabilized receptors, and confirmed by radioligand-binding experiments. Based on a consideration of the requirements for a potential treatment for insomnia, compound 27 was identified as having the best balance of properties from the chemical series. A novel series of potent, selective, and orally efficacious dual antagonists of the orexin receptors is described.