PMID- 29485740
OWN - NLM
STAT- MEDLINE
DCOM- 20190723
LR  - 20231103
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 13
IP  - 10
DP  - 2018 May 23
TI  - Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl 
      Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia.
PG  - 988-1003
LID - 10.1002/cmdc.201700783 [doi]
AB  - 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.
CI  - (c) 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
FAU - Beck, Hartmut
AU  - Beck H
AUID- ORCID: 0000-0002-7826-8467
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Jeske, Mario
AU  - Jeske M
AUID- ORCID: 0000-0002-6680-8948
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Thede, Kai
AU  - Thede K
AD  - Medicinal Chemistry Berlin, Bayer AG, 13342, Berlin, Germany.
FAU - Stoll, Friederike
AU  - Stoll F
AUID- ORCID: 0000-0002-0681-4799
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Flamme, Ingo
AU  - Flamme I
AUID- ORCID: 0000-0003-0855-7850
AD  - Cardiology Research Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Akbaba, Metin
AU  - Akbaba M
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Erguden, Jens-Kerim
AU  - Erguden JK
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Karig, Gunter
AU  - Karig G
AUID- ORCID: 0000-0002-5005-5283
AD  - Medicinal Chemistry Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Keldenich, Jorg
AU  - Keldenich J
AD  - DMPK Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Oehme, Felix
AU  - Oehme F
AD  - Cardiology Research Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Militzer, Hans-Christian
AU  - Militzer HC
AD  - Chemical Development Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
FAU - Hartung, Ingo V
AU  - Hartung IV
AUID- ORCID: 0000-0001-8175-7352
AD  - Medicinal Chemistry Berlin, Bayer AG, 13342, Berlin, Germany.
FAU - Thuss, Uwe
AU  - Thuss U
AUID- ORCID: 0000-0001-8423-2017
AD  - DMPK Wuppertal, Bayer AG, 42096, Wuppertal, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180414
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Pyrazoles)
RN  - 0 (Triazoles)
RN  - 9JH486CZ13 (molidustat)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
MH  - Anemia/*drug therapy/etiology
MH  - Animals
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Drug Discovery
MH  - Humans
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*antagonists & inhibitors
MH  - Kidney Diseases/*complications
MH  - Mice
MH  - Molecular Structure
MH  - Protein Binding
MH  - Protein Conformation
MH  - Pyrazoles/*pharmacology/therapeutic use
MH  - Structure-Activity Relationship
MH  - Triazoles/*pharmacology/therapeutic use
PMC - PMC6001664
OTO - NOTNLM
OT  - BAY 85-3934
OT  - HIF-PH
OT  - inhibitors
OT  - metalloenzymes
OT  - molidustat
EDAT- 2018/02/28 06:00
MHDA- 2019/07/25 06:00
PMCR- 2018/06/14
CRDT- 2018/02/28 06:00
PHST- 2017/12/14 00:00 [received]
PHST- 2018/02/20 00:00 [revised]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2019/07/25 06:00 [medline]
PHST- 2018/02/28 06:00 [entrez]
PHST- 2018/06/14 00:00 [pmc-release]
AID - CMDC201700783 [pii]
AID - 10.1002/cmdc.201700783 [doi]
PST - ppublish
SO  - ChemMedChem. 2018 May 23;13(10):988-1003. doi: 10.1002/cmdc.201700783. Epub 2018 
      Apr 14.