Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases

被引：144
作者：
Joharapurkar, Amit A. [1 ]
Pandya, Vrajesh B. [1 ]
Patel, Vishal J. [1 ]
Desai, Ranjit C. [1 ]
Jain, Mukul R. [1 ]
机构：
[1] Cadila Healthcare Ltd, Zydus Res Ctr, Sarkhej Bavla NH8A, Ahmadabad 382210, Gujarat, India
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 16期
关键词：
HYPOXIA-INDUCIBLE FACTOR; CHRONIC KIDNEY-DISEASE; FACTOR-I HIF-1; ERYTHROPOIETIN PRODUCTION; CRYSTAL-STRUCTURE; IRON-DEFICIENCY; CLINICAL-TRIAL; RENAL ANEMIA; PHASE-I; DOMAIN;
D O I：
10.1021/acs.jmedchem.7b01686
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional, and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia-inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent a novel pharmacological treatment of anemia associated with chronic diseases. Many orally active PHD inhibitors like roxadustat, molidustat, vadadustat, and desidustat are in late phase clinical trials. This review discusses the role of PHD inhibitors in the treatment of anemia associated with chronic diseases.
引用
收藏
页码：6964 / 6982
页数：19
相关论文
共 138 条
[11]   Discovery of Molidustat (BAY85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia [J].
Beck, Hartmut ;
Jeske, Mario ;
Thede, Kai ;
Stoll, Friederike ;
Flamme, Ingo ;
Akbaba, Metin ;
Ergueden, Jens-Kerim ;
Karig, Gunter ;
Keldenich, Joerg ;
Oehme, Felix ;
Militzer, Hans-Christian ;
Hartung, Ingo V. ;
Thuss, Uwe .
CHEMMEDCHEM, 2018, 13 (10) :988-1003
[12]   A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat [J].
Becker, Kimberly ;
Saad, Maha .
ADVANCES IN THERAPY, 2017, 34 (04) :848-853
[13]  
Bembenek S. D, 2010, Patent No. [W02010093727A1, 2010093727]
[14]   Intersecting Guidelines: Administering Erythropoiesis-Stimulating Agents to Chronic Kidney Disease Patients with Cancer [J].
Bennett, Charles L. ;
Becker, Pamela S. ;
Kraut, Eric H. ;
Samaras, Athena T. ;
West, Dennis P. .
SEMINARS IN DIALYSIS, 2009, 22 (01) :1-4
[15]   Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD [J].
Bernhardt, Wanja M. ;
Wiesener, Michael S. ;
Scigalla, Paul ;
Chou, James ;
Schmieder, Roland E. ;
Guenzler, Volkmar ;
Eckardt, Kai-Uwe .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2010, 21 (12) :2151-2156
[16]  
Boettcher M. F., 2013, J AM SOC NEPHROL, V24, p347A
[17]  
Cai J, 2016, Patent No. [W02016049098A1, 2016049098]
[18]  
Cai J, 2016, Patent No. [W02016049099A1, 2016049099]
[19]  
Cai J, 2016, Patent No. [W02016057753A1, 2016057753]
[20]  
Cai J, 2016, [No title captured], Patent No. [W02016049097A1, 2016049097, WO2016049097-A1]
12345678910