Abstract:
: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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
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 Udoi
10.1002/cmdc.201700783subject
Has Abstractpub_date
2018-05-23 00:00:00pages
988-1003issue
10eissn
1860-7179issn
1860-7187journal_volume
13pub_type
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