Health & Environmental Research Online (HERO)


Print Feedback Export to File
7186566 
Journal Article 
Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia 
Beck, H; Jeske, M; Thede, K; Stoll, F; Flamme, I; Akbaba, M; Ergüden, JK; Karig, G; Keldenich, J; Oehme, F; Militzer, HC; Hartung, IV; Thuss, U; , 
2018 
0 
ChemMedChem
ISSN: 1860-7179
EISSN: 1860-7187 
English 
29485740 
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.