Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor.
Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor.
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DOI：
10.1021/ml2002696
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发表时间：
2012-03-08
影响因子：
4.2
通讯作者：
Flaumenhaft, Robert
中科院分区：
文献类型：
--
作者：
Dockendorff, Chris;Aisiku, Omozuanvbo;VerPlank, Lynn;Dilks, James R.;Smith, Daniel A.;Gunnink, Susanna F.;Dowal, Louisa;Negri, Joseph;Palmer, Michelle;MacPherson, Lawrence;Schreiber, Stuart L.;Flaumenhaft, Robert
NIH-MLSMR化合物集合的高通量筛选，沿着一系列二次测定以鉴定命中化合物的潜在靶标，先前鉴定了靶向蛋白酶激活受体1（PAR 1）的1，3-二氨基苯支架。我们现在报告额外的结构-活性关系（SAR）研究，描述了PAR 1活性的要求，并确定了具有PAR 1介导的血小板活化纳摩尔抑制作用的血浆稳定类似物。化合物4被NIH分子库计划宣布为探针（ML 161）。该化合物抑制由PAR 1肽激动剂或凝血酶诱导的血小板聚集，但不抑制由几种其他血小板激动剂诱导的血小板聚集。初步研究表明，ML 161是PAR 1的变构抑制剂。这些发现对于发现具有改善的安全性的抗血栓药物可能是重要的。
A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure–activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile.
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影响因子：
20.3
作者：
Sim, DS;Merrill-Skoloff, G;Flaumenhaft, R
通讯作者：
Flaumenhaft, R
影响因子：
37.8
作者：
O'Donoghue, Michelle L.;Bhatt, Deepak L.;Flather, Marcus D.
通讯作者：
Flather, Marcus D.
DOI：
10.1073/pnas.96.22.12257
发表时间：
1999-10-26
影响因子：
11.1
作者：
Andrade-Gordon, P;Mayanoff, BE;White, KB
通讯作者：
White, KB
影响因子：
37.8
作者：
Wiviott, Stephen D.;Flather, Marcus D.;Bhatt, Deepak L.
通讯作者：
Bhatt, Deepak L.
影响因子：
2.7
作者：
Ahn, HS;Arik, L;Wu, YS
通讯作者：
Wu, YS