Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia.

Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia.

ChemMedChem. 2018 Feb 27;:

Authors: 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

Abstract
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, 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 (1) as a promising hit. The lead optimization programme then resulted in the identification of molidustat (BAY 85 3934, 45), a novel small-molecule oral HIF PH inhibitor. Molidustat is currently being investigated in a clinical phase III trial as molidustat sodium (84) for the treatment of anemia in patients with CKD.

PMID: 29485740 [PubMed - as supplied by publisher]

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