Diabetic retinopathy (DR) is a major cause of blindness, and there is a lack of effective treatment at present. Rho-associated coiled-coil containing serine/threonine protein kinases (ROCKs) have recently been suggested as potential targets for the DR treatment. We herein report the discovery of 4H-chromen-4-one derivatives as a new class of ROCK inhibitors. Structure–activity relationship analyses led to the identification of the most active compound, 4-(dimethylamino)-N-(3-{2-[(4-oxo-4H-chromen-7-yl)oxy]acetamido}phenyl) (12j). This compound showed excellent kinase selectivity for ROCK I and ROCK II against 387 other kinases. In retinal explants, compound 12j protected retinal neurons from high glucose-induced oxidative stress and apoptosis-mediated cell death. Furthermore, 12j administration suppressed the improper proliferation of Müller cells and promoted the regression of vascular vessels in retinal explants cultured in a high glucose microenvironment. Collectively, our data suggest that 12j could be a potential lead compound for the treatment of DR, hence deserving further in-depth studies.

中文翻译：

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发现4H-Chromen-4-one衍生物作为新型的选择性Rho激酶（ROCK）抑制剂，在体外糖尿病性视网膜病变模型中显示出强效活性。

糖尿病性视网膜病（DR）是失明的主要原因，目前缺乏有效的治疗方法。最近，有人建议将含有丝氨酸/苏氨酸蛋白激酶（ROCKs）的Rho相关卷曲螺旋作为DR治疗的潜在靶标。我们在此报告了发现4 H -chromen-4-one衍生物作为一类新的ROCK抑制剂的发现。结构-活性关系分析导致鉴定出活性最高的化合物4-（二甲基氨基）-N-（3- {2-[（4-oxo-4 H -chromen-7-yl）oxy] acetamido} phenyl） （12j）。该化合物对ROCK I和ROCK II对387种其他激酶具有出色的激酶选择性。在视网膜外植体中，化合物12j保护视网膜神经元免受高葡萄糖诱导的氧化应激和凋亡介导的细胞死亡。此外，在高葡萄糖微环境下培养的视网膜外植体中，12j给药抑制了Müller细胞的不适当增殖，并促进了血管的退化。总体而言，我们的数据表明12j可能是治疗DR的潜在先导化合物，因此值得进一步深入研究。