Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis

被引：56

作者：

Kim, Kyung-Hee ^{[1
]}

Maderna, Andreas ^{[1
]}

Schnute, Mark E. ^{[1
]}

Hegen, Martin ^{[2
]}

Mohan, Shashi ^{[2
]}

Miyashiro, Joy ^{[2
]}

Lin, Laura ^{[2
]}

Li, Evelyn ^{[2
]}

Keegan, Sean ^{[2
]}

Lussier, Jennifer ^{[2
]}

Wrocklage, Christopher ^{[2
]}

Nickerson-Nutter, Cheryl L. ^{[2
]}

Wittwer, Arthur J. ^{[2
]}

Soutter, Holly ^{[3
]}

Caspers, Nicole ^{[3
]}

Han, Seungil ^{[3
]}

Kurumbail, Ravi ^{[3
]}

Dunussi-Joannopoulos, Kyri ^{[2
]}

Douhan, John, III ^{[2
]}

Wissner, Allan ^{[1
]}

机构：

[1] Pfizer, Med Chem, Cambridge, MA 02140 USA

[2] Pfizer, Inflammat & Autoimmun, Cambridge, MA 02140 USA

[3] Pfizer Inc, Struct Biol & Biophys, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 21期

关键词：

BTK; Autoimmune; Rheumatoid arthritis; Covalent kinase inhibitor; Imidazo[1,5-a]quinoxaline; TYROSINE KINASE; B-CELL; DESIGN; POTENT; STRATEGY; DOMAIN; MICE;

D O I：

10.1016/j.bmcl.2011.09.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6258 / 6263

页数：6

共 21 条

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