Structure-baseddrug design was used to guide the optimizationof a series of selective BTK inhibitors as potential treatments forRheumatoid arthritis. Highlights include the introduction of a benzylalcohol group and a fluorine substitution, each of which resultedin over 10-fold increase in activity. Concurrent optimization of drug-likeproperties led to compound 1(RN486) (J. Pharmacol. Exp. Ther.2012, 341, 90),which was selected for advanced preclinical characterization basedon its favorable properties. [ABSTRACT FROM AUTHOR]