Sate Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Laboratory of Drug Design and Discovery, Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2021 Dec 9;64(23):17384-17402. doi: 10.1021/acs.jmedchem.1c01479. Epub 2021 Oct 28.
Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC = 490 nM, = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that could allosterically enhance HIF-2 dimerization. Furthermore, compound had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an safety profile (the LD in mice was greater than 708 mg·kg). In the efficacy assays, the combination of and the prolyl hydroxylase inhibitor, , was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.
缺氧诱导因子 2 (HIF-2) 的激活已成为一种有效的肾脏贫血治疗策略。本文首次报道了苯并异噻唑衍生物 是一种新型的 HIF-2α激动剂，在荧光素酶报告基因检测中具有纳摩尔级的活性（EC = 490 nM， = 349.2%）。分子动力学模拟表明， 可以别构增强 HIF-2 二聚体化。此外，化合物 具有良好的药代动力学特性（大鼠口服生物利用度为 41.38%）和安全性特征（小鼠 LD 大于 708 mg·kg）。在 功效检测中，首次证实了 与脯氨酰羟化酶抑制剂 的联合使用可协同增加小鼠血浆促红细胞生成素水平（从 260 增加到 2296 pg·mL）并缓解多柔比星诱导的斑马鱼贫血。这些结果为 HIF-2α 激动剂和肾脏贫血的治疗提供了新的见解。
