scholarly journals Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor–Prolyl Hydroxylase Inhibitor for Anemia

2017 ◽  
Vol 363 (3) ◽  
pp. 336-347 ◽  
Author(s):  
Jennifer L. Ariazi ◽  
Kevin J. Duffy ◽  
David F. Adams ◽  
Duke M. Fitch ◽  
Lusong Luo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Inhibitor

scholarly journals A Novel Hypoxia-Inducible Factor−Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

2016 ◽  
Vol 67 (6) ◽  
pp. 861-871 ◽  
Author(s):  
Richard A. Brigandi ◽  
Brendan Johnson ◽  
Coreen Oei ◽  
Mark Westerman ◽  
Gordana Olbina ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Inhibitor

Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites

2011 ◽  
Vol 436 (2) ◽  
pp. 363-369 ◽  
Author(s):  
Melissa B. Pappalardi ◽  
Dean E. McNulty ◽  
John D. Martin ◽  
Kelly E. Fisher ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Transactivation Domain ◽  
Prolyl Hydroxylases ◽  
Proline Residue ◽  
Protein Substrates ◽  
Steady State Kinetic ◽  
Asparaginyl Hydroxylase

The HIF (hypoxia-inducible factor) plays a central regulatory role in oxygen homoeostasis. HIF proteins are regulated by three Fe(II)- and α-KG (α-ketoglutarate)-dependent prolyl hydroxylase enzymes [PHD (prolyl hydroxylase domain) isoenzymes 1–3 or PHD1, PHD2 and PHD3] and one asparaginyl hydroxylase [FIH (factor inhibiting HIF)]. The prolyl hydroxylases control the abundance of HIF through oxygen-dependent hydroxylation of specific proline residues in HIF proteins, triggering subsequent ubiquitination and proteasomal degradation. FIH inhibits the HIF transcription activation through asparagine hydroxylation. Understanding the precise roles and regulation of these four Fe(II)- and α-KG-dependent hydroxylases is of great importance. In the present paper, we report the biochemical characterization of the first HIF protein substrates that contain the CODDD (C-terminal oxygen-dependent degradation domain), the NODDD (N-terminal oxygen-dependent degradation domain) and the CAD (C-terminal transactivation domain). Using LC-MS/MS (liquid chromatography–tandem MS) detection, we show that all three PHD isoenzymes have a strong preference for hydroxylation of the CODDD proline residue over the NODDD proline residue and the preference is observed for both HIF1α and HIF2α protein substrates. In addition, steady-state kinetic analyses show differential substrate selectivity for HIF and α-KG in reference to the three PHD isoforms and FIH.

scholarly journals SO052EFFECT OF SEVERE RENAL IMPAIRMENT OR END-STAGE RENAL DISEASE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ROXADUSTAT, AN ORAL HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITOR

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dorien Groenendaal-van de Meent ◽  
Virginie Kerbusch ◽  
Rudiger Kaspera ◽  
Begona Barroso-Fernandez ◽  
Piergiorgio Galletti ◽  
...  
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Severe Renal Impairment ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Least Square ◽  
Maximum Effect ◽  
Prolyl Hydroxylase Inhibitor ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor used at titrated doses to treat anaemia in CKD patients. This study investigated the pharmacokinetics (PK), metabolic profile, pharmacodynamics, and safety of roxadustat in subjects with different degrees of renal function (RF). Method This was a phase 1, open-label study conducted in Germany and the United Kingdom (EudraCT Number: 2015-002565-28). Subjects were enrolled in four RF groups: normal RF (eGFR ≥90 mL/min/1.73 m2); severely impaired RF (not on dialysis; eGFR <30 mL/min/1.73 m2); end-stage renal disease (ESRD) on continuous ambulatory or automated peritoneal dialysis (CAPD/APD); or ESRD on 4-hour haemodialysis or haemodiafiltration (HD/HDF). Subjects in the normal RF, severely impaired RF, and ESRD on CAPD/APD groups received a single dose of 100-mg oral roxadustat on Day 1. A single-sequence design with two treatment periods (P1/P2) separated by a washout period was used for subjects with ESRD on HD/HDF; a single administration of 100-mg oral roxadustat occurred 2 hours after completion of a HD/HDF session (P1) and 2 hours before initiation of a HD/HDF session, 2 days after the previous session (P2). Plasma and urine PK of roxadustat and its circulating metabolites (O-glucuronide-, O-glucoside-, and sulphate of hydroxy-roxadustat) and plasma erythropoietin (EPO) were evaluated. Continuous heart rate monitoring was conducted. Results Of 73 screened subjects, 34 (46.6%) were enrolled and received roxadustat (normal RF, n=12; severely impaired RF, n=9; ESRD on CAPD, n=1; ESRD on HD/HDF, n=12). The geometric least-square mean ratio of area under the plasma concentration-time curve (AUC) from administration to infinity (AUCinf) relative to subjects with normal RF was 223% (90% CI: 185, 268) and 195% (90% CI: 165, 229) in subjects with severely impaired RF and in those with ESRD on HD/HDF, respectively. Roxadustat’s maximum concentration (Cmax) and terminal elimination half-life (t1/2) were comparable between groups. The PK of roxadustat and its metabolites were not affected by HD/HDF. In subjects with normal RF, the amount of roxadustat excreted unchanged in urine was <1%; urinary excretion and renal clearance of roxadustat and its metabolites decreased with lower baseline RF. Mean AUCinf and t1/2 for roxadustat’s circulating metabolites were higher in subjects with severely impaired RF and with ESRD on HD/HDF than in those with normal RF. Metabolite to parent ratio of AUCinf was <1% for O-glucuronide- and O-glucoside-roxadustat and <10% for sulphate of hydroxy-roxadustat. EPO baseline-corrected AUC from administration to last measurable concentration and EPO maximum effect were higher in subjects with severely impaired RF or with ESRD on HD/HDF than in those with normal RF. Conclusion The AUC for roxadustat and its metabolites was higher in patients with severely impaired RF or with ESRD on HD/HDF than in those with normal RF. Roxadustat’s Cmax and t1/2 were comparable among all groups. Roxadustat and its metabolites were not significantly cleared by HD/HDF.

Hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat (FG-4592) alleviates sepsis-induced acute lung injury

2020 ◽  
Vol 281 ◽  
pp. 103506
Author(s):  
Fu Han ◽  
Gaofeng Wu ◽  
Shichao Han ◽  
Zhenzhen Li ◽  
Yanhui Jia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Inhibitor
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