Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
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DOI：
10.1021/jm4013888
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发表时间：
2013-12-12
影响因子：
7.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Zhang W;McIver AL;Stashko MA;DeRyckere D;Branchford BR;Hunter D;Kireev D;Miley MJ;Norris-Drouin J;Stewart WM;Lee M;Sather S;Zhou Y;Di Paola JA;Machius M;Janzen WP;Earp HS;Graham DK;Frye SV;Wang X
The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo-ring replacement strategy. The co-crystal structure of Mer with two compounds (7 & 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.
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影响因子：
4.2
作者：
Liu, Jing;Yang, Chao;Simpson, Catherine;DeRyckere, Deborah;Van Deusen, Amy;Miley, Michael J.;Kireev, Dmitri;Norris-Drouin, Jacqueline;Sather, Susan;Hunter, Debra;Korboukh, Victoria K.;Patel, Hari S.;Janzen, William P.;Machius, Mischa;Johnson, Gary L.;Earp, H. Shelton;Graham, Douglas K.;Frye, Stephen V.;Wang, Xiaodong
通讯作者：
Wang, Xiaodong
影响因子：
--
作者：
Bernasconi, Paul;Chen, Min;Janzen, William P.
通讯作者：
Janzen, William P.
影响因子：
--
作者：
Pommereau, A;Pap, E;Kannt, A
通讯作者：
Kannt, A
影响因子：
2.7
作者：
Zhang, Guobao;Ren, Pingda;He, Yun
通讯作者：
He, Yun
影响因子：
168.9
作者：
Diener, HC;Bogousslavsky, J;Rupprecht, HJ
通讯作者：
Rupprecht, HJ