Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors

Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure–activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.

Graphical abstractBased on the understanding on the binding structures of two lead COX-2 inhibitor, SD-8381 and Celecoxib, the combination of structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly establish the structure–activity/property relationship of benzopyran COX-2 inhibitors and identify potent and selective new lead compounds with improved metabolic properties. Free energy perturbation prediction yielded insights into binding free energies that guide inhibitor design.Figure optionsDownload full-size imageDownload as PowerPoint slide