An mGlu5 NAM pre-clinical candidate molecule has been identified through fragment-based drug discovery using a stabilised receptor (StaR). The candidate has more than ten-fold better affinity and ED50 in an ex vivo receptor occupancy model than mavoglurant, the most advanced clinical mGlu5 NAM, and has a significantly superior in vivoPK profile in rat and dog. Excellent selectivity within the mGlu receptor sub-family is matched by a clean profile against an extensive panel of CNS targets. Details of the data package associated with the candidate molecule will be disclosed.The G protein-coupled receptor (GPCR) superfamily is critically involved in many diseases and has been a drug-discovery focus for decades, with approximately 30% of current drugs modulating these important targets. Despite this, many receptors with good pre-clinical or clinical validation have been difficult to prosecute using traditional strategies. Instability of GPCRs when removed from their membrane environment has severely limited the application of fragment-based techniques, an issue overcome at Heptares by generation of stabilised receptors (StaR proteins) which facilitate biophysical and biochemical fragment screening and allow X-ray structural information to be obtained.In the first application of our approach to a family C target, an mGlu5 StaR has been created, using a NAM ligand to introduce a conformational bias towards the desired pharmacology for subsequent drug discovery. Enhanced stability of the mGlu5 StaR, coupled with dramatically increased expression and significantly higher DMSO tolerance, allowed us to conduct a robust fragment screen. The screen, in high-concentration radioligand binding format, yielded high-quality hits from a family C focused set and the general Heptares fragment collection. The most favourable series was rapidly advanced in a hit to lead to candidate process lasting approximately one year with less than 100 compounds synthesized before candidate identification.

Fragment-based GPCR drug discovery using a stabilised receptor (StaR): Identification of an mGlu5 negative allosteric modulator (NAM) pre-clinical candidate

247th National Meeting (2014)

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