Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia
Background: Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are being explored in clinical development as novel therapies for anemia associated with chronic kidney disease (CKD). Inhibition of HIF-PH mimics hypoxia, leading to increased erythropoietin (EPO) production and enhanced erythropoiesis.
Methods: This study outlines the discovery, synthesis, structure-activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones, designed as orally bioavailable HIF-PH inhibitors for treating anemia. High-throughput screening of our corporate compound library led to the identification of BAY-908 as a promising lead compound. Subsequent lead optimization culminated in the identification of molidustat (BAY 85-3934), a novel oral small-molecule HIF-PH inhibitor.
Results: Molidustat is currently undergoing clinical phase III trials as molidustat sodium for the treatment of anemia in CKD patients.
Conclusions: Our findings highlight the development of molidustat as an effective oral HIF-PH inhibitor, with ongoing clinical investigations into its potential for treating anemia in CKD.