Glucocorticoid receptor (GR) agonists are one of the most widely prescribed for the treatment of inflammatory diseases such as rheumatoid arthritis and asthma. However their therapeutic usages are limited by their severe side effects. We identified a novel series of indole-based GR ligands with trifluoromethylcarbinol moiety which has been introduced as a key structural motif on non-steroidal GR agonists. Our prototype ligands showed moderate binding affinities and antagonistic activities. Further extensive structural characterizations succeeded in converting from antagonists into agonists by installing the substituted cyclic amine moiety, which could interact with Gln642 and Thr739 in GR ligand binding pocket. Our de novo design strategy with the insights of computational docking simulations will be described in detail.

Design of de novo glucocorticoid receptor agonist: Chemical manipulation to transform indole derivatives from antagonist into agonist

244th National Meeting (2012)

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