Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis

被引：95

作者：

Lou, Yan ^{[1
]}

Han, Xiaochun ^{[1
]}

Kuglstatter, Andreas ^{[1
]}

Kondru, Rama K. ^{[1
]}

Sweeney, Zachary K. ^{[1
]}

Soth, Michael ^{[1
]}

McIntosh, Joel ^{[1
]}

Litman, Renee ^{[1
]}

Suh, Judy ^{[1
]}

Kocer, Buelent ^{[1
]}

Davis, Dana ^{[1
]}

Park, Jaehyeon ^{[1
]}

Frauchiger, Sandra ^{[1
]}

Dewdney, Nolan ^{[1
]}

Zecic, Hasim ^{[1
]}

Taygerly, Joshua P. ^{[1
]}

Sarma, Keshab ^{[1
]}

Hong, Junbae ^{[1
]}

Hill, Ronald J. ^{[1
]}

Gabriel, Tobias ^{[1
]}

Goldstein, David M. ^{[1
]}

Owens, Timothy D. ^{[1
]}

机构：

[1] Hoffmann La Roche Inc, Discovery Chem, Small Mol Res, PRED, Palo Alto, CA 94304 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 01期

关键词：

B-CELL; JAK INHIBITOR; DISCOVERY; DISEASES;

D O I：

10.1021/jm500305p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：512 / 516

页数：5

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