Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases

被引：36

作者：

Shi, Qing ^{[1
]}

Tebben, Andrew ^{[1
]}

Dyckman, Alaric J. ^{[1
]}

Li, Hedy ^{[1
]}

Liu, Chunjian ^{[1
]}

Lin, James ^{[1
]}

Spergel, Steve ^{[1
]}

Burke, James R. ^{[1
]}

McIntyre, Kim W. ^{[1
]}

Olini, Gilbert C. ^{[1
]}

Strnad, Joann ^{[1
]}

Surti, Neha ^{[1
]}

Muckelbauer, Jodi K. ^{[1
]}

Chang, Chiehying ^{[1
]}

An, Yongmi ^{[1
]}

Cheng, Lin ^{[1
]}

Ruan, Qian ^{[1
]}

Leftheris, Katerina ^{[1
]}

Carter, Percy H. ^{[1
]}

Tino, Joseph ^{[1
]}

De Lucca, George V. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 09期

关键词：

BTK; Autoimmune diseases; Purine; DRUG DISCOVERY; ACTIVATION; REARRANGEMENT; ARTHRITIS; RESPONSES; GENE; MICE;

D O I：

10.1016/j.bmcl.2014.02.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：2206 / 2211

页数：6

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