The orexin receptors (OX1 and OX2) are G protein-coupled receptors (GPCRs) that are validated drug targets for the treatment of conditions such as sleep disorders and addictive or compulsive behaviours.  Innovative medicinal chemistry approaches are required to develop CNS-active drugs for these receptors given that their endogenous ligands (orexin-A and orexin-B) are high molecular weight neuropeptides comprising 33 and 28 amino acid residues, respectively.Heptares applies structure-based drug design approaches to GPCRs using its StaR platform. StaR proteins have a significantly increased thermostability when compared to the wild-type receptors and this enables the application of techniques such as X-ray crystallography, biophysical methods and high concentration fragment screening, which are typically not compatible with these challenging membrane-bound receptors.  The 3D structures of many GPCRs have been determined by applying StaR technology, including the first crystal structure of a family B GPCR. A case study will be presented in which these methods were applied to the discovery of a series of 2H-1,2-4-benzothiadiazin-3(4H)-one 1,1-dioxide derivatives as dual orexin receptor antagonists (DORAs).  Co-crystal structures with OX1 and OX2 will be described, along with structure-based design aspects of the program, target engagement studies, and details of pharmacokinetics and in vivo efficacy of the lead molecules.� Heptares Therapeutics 2014The HEPTARES name, the logo and StaR are trademarks of Heptares Therapeutics Ltd

Discovery of 2<i>H</i>-1,2-4-benzothiadiazin-3(4<i>H</i>)-one 1,1-dioxide derivatives as orexin receptor antagonists by structure-based drug design

248th National Meeting (2014)

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Discovery of 2H-1,2-4-benzothiadiazin-3(4H)-one 1,1-dioxide derivatives as orexin receptor antagonists by structure-based drug design