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Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia
Author(s) -
Beck Hartmut,
Jeske Mario,
Thede Kai,
Stoll Friederike,
Flamme Ingo,
Akbaba Metin,
Ergüden JensKerim,
Karig Gunter,
Keldenich Jörg,
Oehme Felix,
Militzer HansChristian,
Hartung Ingo V.,
Thuss Uwe
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700783
Subject(s) - anemia , erythropoietin , hypoxia inducible factors , kidney disease , hypoxia (environmental) , bioavailability , pharmacology , erythropoiesis , biology , medicine , chemistry , biochemistry , gene , oxygen , organic chemistry
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‐3 H ‐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.