Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors.,Bioorganic & Medicinal Chemistry Letters

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Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-01-15 , DOI: 10.1016/j.bmcl.2020.126966
Zhuang Miao ₁ , Yu-Meng Sun ₂ , Lan-Ying Zhao ₁ , Yue-Shan Li ₁ , Yi-Fei Wang ₂ , Jin-Shan Nan ₁ , Ze-En Qiao ₁ , Lin-Li Li ₂ , Sheng-Yong Yang ₁

Affiliation

Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 μM and 0.001 μM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs.

中文翻译：

硫代[2,3-d]嘧啶-4（3H）-一衍生物的发现作为一类新型的ROCK抑制剂。

在本文中，我们报告了一系列噻吩[2,3-d]嘧啶-4（3H）-一衍生物作为一类新的ROCK抑制剂的发现。这些化合物的结构活性关系研究导致最有效的化合物，3-（3-甲氧基苄基）-6-（1H-吡咯并[2,3-b]吡啶-4-基）噻吩并[2,3]的鉴定-d] pyrimidin-4（3H）-one（8k），对ROCKⅠ和ROCKⅡ的IC50值分别为0.004μM和0.001μM。在体外，8k显着降低了ROCK下游信号蛋白的磷酸化水平，并诱导细胞形态和迁移的改变。总体而言，这项研究为靶向ROCKs的药物发现提供了有希望的先导化合物。

更新日期：2020-01-15

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