Download MendeleyStructure-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, R.K., Sweeney, Z.K., Soth, M., McIntosh, J., Litman, R., Suh, J., Kocer, B., Davis, D., Park, J., Frauchiger, S., Dewdney, N., Zecic, H., Taygerly, J.P., Sarma, K., Hong, J., Hill, R.J., Gabriel, T., Goldstein, D.M., Owens, T.D.(2015) J Med Chem 58: 512-516
- PubMed: 24712864
- DOI: https://doi.org/10.1021/jm500305p
- Primary Citation of Related Structures:
4OT5, 4OT6, 4OTQ, 4OTR - PubMed Abstract:
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.
Organizational Affiliation:
pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, Hoffmann-La Roche Inc. , 3431 Hillview Avenue, Palo Alto, California 94304, United States.
