PAR2 is a G-protein coupled receptor (GPCR) known to mediate inflammatory pathways and is implicated in several diseases such as pain, airway inflammation, and skin disorders.  We report a novel series of antagonists discovered by DEL screening of purified and stabilized PAR2. Optimization of this series resulted in potent and selective compounds which demonstrated antagonism across a range of PAR2 cellular models. The crystal structure of the stabilized receptor in complex with a member of this series revealed an allosteric binding mode at the surface of the receptor within the hydrophobic membrane spanning region. In addition, another series was identified by DEL screening of an unknown binding mode.  Chemical expansion of this series resulted in potent and selective agonists of PAR2. Thus, DEL screening in combination with GPCR stabilization technology and crystallography, has led to novel antagonists and agonists of PAR2.   These compounds have proven to be useful tools in helping to understand the complex pharmacology of this receptor.    <br/>

Discovery of small molecule protease-activated receptor 2 (PAR2) antagonists and agonists using DNA-encoded library (DEL) screening technologies

254th National Meeting (2017)

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