帕莫杜林 NRD-21 是一种 PAR1 Gq 信号的别构抑制剂，具有改善的抗炎活性和稳定性。
The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability.
机构信息
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.
出版信息
Bioorg Med Chem. 2019 Sep 1;27(17):3788-3796. doi: 10.1016/j.bmc.2019.06.043. Epub 2019 Jun 29.
Abstract
Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.
摘要
为了鉴定具有改善特性的新型、变构、偏向 PAR1 配体 ML161（帕莫杜林 2，PM2）类似物，我们制备了该配体的西部 1,3-二氨基苯骨架的新型类似物。我们使用内皮细胞内钙动员测定法研究了该骨架的结构-活性关系，鉴定出了几种能以亚微摩尔浓度抑制 PAR1 的杂环化合物。我们进一步详细研究了唑 NRD-21，证实它是 PAR1 的选择性、可逆、负变构调节剂。除了抑制人血小板聚集外，在 qPCR 测定中，它在细胞因子 TNF-α刺激内皮细胞组织因子表达方面显示出优于 ML161 的抗炎活性。此外，NRD-21 比 ML161 更稳定，在血浆中更稳定，是抗血栓和抗炎适应症的帕莫杜林类有前途的先导化合物。
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