Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

被引：27

作者：

Haile, Pamela A. ^{[1
]}

Casillas, Linda N. ^{[1
]}

Bury, Michael J. ^{[1
]}

Mehlmann, John F. ^{[1
]}

Singhaus, Robert, Jr. ^{[1
]}

Charnley, Adam K. ^{[1
]}

Hughes, Terry V. ^{[1
]}

DeMartino, Michael P. ^{[1
]}

Wang, Gren Z. ^{[1
]}

Romano, Joseph J. ^{[1
]}

Dong, Xiaoyang ^{[1
]}

Plotnikov, Nikolay V. ^{[1
]}

Lakdawala, Ami S. ^{[1
]}

Convery, Maire A. ^{[2
]}

Votta, Bartholomew J. ^{[1
]}

Lipshutz, David B. ^{[1
]}

Desai, Biva M. ^{[1
]}

Swift, Barbara ^{[1
]}

Capriotti, Carol A. ^{[1
]}

Berger, Scott B. ^{[1
]}

Mahajan, Mukesh K. ^{[1
]}

Reilly, Michael A. ^{[1
]}

Rivera, Elizabeth J. ^{[1
]}

Sun, Helen H. ^{[1
]}

Nagilla, Rakesh ^{[1
]}

LePage, Carol ^{[1
]}

Ouellette, Michael T. ^{[1
]}

Totoritis, Rachel D. ^{[1
]}

Donovan, Brian T. ^{[1
]}

Brown, Barry S. ^{[1
]}

Chaudhary, Khuram W. ^{[1
]}

Gough, Peter J. ^{[1
]}

Bertin, John ^{[1
]}

Marquis, Robert W. ^{[1
]}

机构：

[1] GlaxoSmithKline, Collegeville Rd, Collegeville, PA 19426 USA

[2] GlaxoSmithKline, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 10期

关键词：

RIP2; NOD1; NOD2; kinase inhibitor; hERG; DRUGS; ASSOCIATION; DISEASE; POTENT;

D O I：

10.1021/acsmedchemlett.8b00344

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 mu M).

引用

页码：1039 / 1044

页数：11

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