Structure-based optimization of a potent class of arylamide FMS inhibitors

An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.

Graphical abstractPotent FMS inhibitors possessing a 1,2,4-phenylenetriamine core structure were optimized with the aid of structure-based modeling to alleviate the potential for quinonediimine reactive intermediate formation and to obtain equally potent FMS inhibitors with no detectable IDR liability.Figure optionsDownload full-size imageDownload as PowerPoint slide