Scaffold hopping strategy to derive 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b′]dipyridine-3-carbonylglycine derivatives as a novel hypoxia-inducible factor prolyl hydroxylase domain inhibitor for the potential treatment of chronic kidney disease anemia,Bulletin of the Korean Chemical Society

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Scaffold hopping strategy to derive 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b′]dipyridine-3-carbonylglycine derivatives as a novel hypoxia-inducible factor prolyl hydroxylase domain inhibitor for the potential treatment of chronic kidney disease anemia
Bulletin of the Korean Chemical Society ( IF 2.3 ) Pub Date : 2023-01-19 , DOI: 10.1002/bkcs.12652
Ga Young Park _{1,

2} , Cheoul‐Hong Park ₃ , Sang Kwang Lee ₁ , Chun Young Im ₁ , Soong‐Hyun Kim ₁ , Hee Jong Hwang ₁ , Jieon Lee ₁ , Taeho Lee ₂ , Yong Rae Hong ₃ , Minsoo Song ₁

Affiliation

Derivatives of 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b′]dipyridine-3-carbonylglycine were developed as a novel hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibitor. The chemical space of the tricyclic 4-hydroxypyridinyl glycines was examined thoroughly during our optimization study. One of our most potent compounds 12ar exhibits superior enzymatic activity to the known PHD inhibitors that are in the late stage of clinical studies. The functional efficacy of our PHD inhibitors was confirmed via the increased level of erythropoietin (EPO) expression in a dose-dependent manner in vitro.

中文翻译：

支架跳跃策略衍生 4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b']dipyridine-3-carbonylglycine 衍生物作为新型缺氧诱导因子脯氨酰用于治疗慢性肾病贫血的羟化酶结构域抑制剂

4-hydroxy-1-alkyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b']dipyridine-3-carbonylglycine 的衍生物被开发为新型缺氧诱导因子脯氨酰羟化酶结构域(PHD) 抑制剂。在我们的优化研究期间，彻底检查了三环 4-羟基吡啶基甘氨酸的化学空间。我们最有效的化合物之一12ar表现出优于处于临床研究后期的已知 PHD 抑制剂的酶活性。我们的 PHD 抑制剂的功能功效通过体外剂量依赖性方式增加的促红细胞生成素 (EPO) 表达水平得到证实。

更新日期：2023-01-19

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