Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis
Lou, Y; Han, X; Kuglstatter, A; Kondru, RK; Sweeney, ZK; Soth, M; Mcintosh, J; Litman, R; Suh, J; Kocer, B; Davis, D; Park, J; Frauchiger, S; Dewdney, N; Zecic, H; Taygerly, JP; Sarma, K; Hong, J; Hill, RJ; Gabriel, T; Goldstein, DM; Owens, TD
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.