Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemias
Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemias
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DOI：
10.1124/jpet.117.242503
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发表时间：
2017-12-01
影响因子：
3.5
通讯作者：
Erickson-Miller, Connie
中科院分区：
文献类型：
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作者：
Ariazi, Jennifer L.;Duffy, Kevin J.;Erickson-Miller, Connie
促红细胞生成素 (EPO) 生成减少、红细胞存活时间缩短以及其他降低 EPO 反应的因素会导致患有慢性肾病等多种潜在疾病的患者出现贫血。超生理浓度的重组人 EPO (rHuEPO) 治疗已被证明是有效的。然而，它并不能改善所有患者的病情，而且有其自身的风险，包括心血管并发症。转录因子缺氧诱导因子 (HIF) 1 α 和 HIF2 α 控制对缺氧的生理反应并启动增加红细胞生成的程序。 HIF α 水平通过 HIF-脯氨酰羟化酶 (PHD) 家族的作用受到氧张力的调节，这些酶标记 HIFa 进行蛋白酶体降解。对这些 PHD 的抑制模拟轻度缺氧的条件，导致潜在的更生理性的红细胞生成反应，并提供高剂量 rHuEPO 的潜在替代方案。在这里，我们描述了 GSK1278863 [2-(1,3-二环己基-6-羟基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰胺基)乙酸]的发现和表征，它是一种 PHD 1-3 的嘧啶三酮-甘氨酰胺低纳摩尔抑制剂，可稳定 HIF α 在细胞系中，导致 EPO 水平增加。在正常小鼠中，单剂量的 GSK1278863 诱导循环血浆 EPO 显着增加，但血浆血管内皮生长因子 (VEGF-A) 浓度仅略有增加。每日一次口服给药后，GSK1278863 显着增加临床前物种的网织红细胞和红细胞质量参数，并表现出可接受的非临床毒性特征，支持持续的临床开发。 GSK1278863目前正处于治疗慢性肾病患者贫血的3期临床试验中。
Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1 alpha and HIF2 alpha control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIF alpha are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFa for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIF alpha in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.