Journal
CHEMMEDCHEM
Volume 13, Issue 10, Pages 988-1003Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700783
Keywords
BAY85-3934; HIF-PH; inhibitors; metalloenzymes; molidustat
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Funding
- Bayer AG
- Bayer AG, Wuppertal, Germany
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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 (BAY85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phaseIII trials as molidustat sodium for the treatment of anemia in patients with CKD.
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