Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

被引：31

作者：

Blomgren, Peter ^{[1
]}

Chandrasekhar, Jayaraman ^{[1
]}

Di Paolo, Julie A. ^{[2
]}

Fung, Wanchi ^{[2
]}

Geng, Guoju ^{[2
]}

Ip, Carmen ^{[2
]}

Jones, Randall ^{[1
]}

Kropf, Jeffrey E. ^{[1
]}

Lansdon, Eric B. ^{[2
]}

Lee, Seung ^{[1
]}

Lo, Jennifer R. ^{[1
]}

Mitchell, Scott A. ^{[1
]}

Murray, Bernard ^{[2
]}

Pohlmeyer, Chris ^{[2
]}

Schmitt, Aaron ^{[1
]}

Suekawa-Pirrone, Kimberly ^{[2
]}

Wise, Sarah ^{[2
]}

Xiong, Jin-Ming ^{[1
,2
]}

Xu, Jianjun ^{[1
,2
]}

Yu, Helen ^{[2
]}

Zhao, Zhongdong ^{[1
,2
]}

Currie, Kevin S. ^{[1
]}

机构：

[1] Gilead Sci, Seattle, WA 98102 USA

[2] Gilead Sci, Foster City, CA 94404 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 04期

关键词：

SYK; kinase inhibitor; solubility; lupus; SYK; ENTOSPLETINIB; GS-9973; POTENT;

D O I：

10.1021/acsmedchemlett.9b00621

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

引用

页码：506 / 513

页数：8

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