Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis

被引：112

作者：

Harris, Philip A. ^{[1
]}

Bandyopadhyay, Deepak ^{[2
]}

Berger, Scott B. ^{[1
]}

Campobasso, Nino ^{[2
]}

Capriotti, Carol A. ^{[1
]}

Cox, Julie A. ^{[2
]}

Dare, Lauren ^{[1
]}

Finger, Joshua N. ^{[1
]}

Hoffman, Sandra J. ^{[1
]}

Kahler, Kirsten M. ^{[3
]}

Lehr, Ruth ^{[2
]}

Lich, John D. ^{[1
]}

Nagilla, Rakesh ^{[1
]}

Nolte, Robert T. ^{[3
]}

Ouellette, Michael T. ^{[2
]}

Pao, Christina S. ^{[2
]}

Schaeffer, Michelle C. ^{[1
]}

Smallwood, Angela ^{[2
]}

Sun, Helen H. ^{[1
]}

Swift, Barbara A. ^{[1
]}

Totoritis, Rachel D. ^{[2
]}

Ward, Paris ^{[2
]}

Marquis, Robert W. ^{[1
]}

Bertin, John ^{[1
]}

Gough, Peter J. ^{[1
]}

机构：

[1] GlaxoSmithKline, Pattern Recognit Receptor DPU, Collegeville, PA 19426 USA

[2] GlaxoSmithKline, Platform Technol & Sci, Collegeville, PA 19426 USA

[3] GlaxoSmithKline, Platform Technol & Sci, Res Triangle Pk, NC 27709 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 12期

关键词：

RIP1; type II kinase inhibitors; necroptosis; ISCHEMIA/REPERFUSION INJURY; INFLAMMATORY RESPONSE; CELL-DEATH; NECROSIS; NECROSTATINS; CONTRIBUTES; LETHAL; AGENT;

D O I：

10.1021/ml400382p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNF alpha induced lethal shock.

引用

页码：1238 / 1243

页数：6

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