Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
Medicinal Chemistry Berlin, Bayer AG, 13342, Berlin, Germany.
ChemMedChem. 2018 May 23;13(10):988-1003. doi: 10.1002/cmdc.201700783. Epub 2018 Apr 14.
Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure-activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.
小分子缺氧诱导因子脯氨酰羟化酶（HIF-PH）抑制剂目前正在临床开发中，作为治疗慢性肾脏病（CKD）相关贫血的新型治疗选择。HIF-PH 的抑制作用模拟缺氧，导致促红细胞生成素（EPO）表达增加，随后红细胞生成增加。本文描述了新型 2,4-二杂芳基-1,2-二氢-3H-吡唑-3-酮作为口服生物利用的 HIF-PH 抑制剂的发现、合成、构效关系（SAR）和拟议结合模式，用于治疗贫血。我们公司化合物库的高通量筛选确定 BAY-908 为有前途的候选药物。随后的先导优化计划确定了莫立司他（BAY 85-3934），这是一种新型小分子口服 HIF-PH 抑制剂。莫立司他目前正在进行临床 III 期试验，作为莫立司他钠治疗 CKD 患者的贫血。
