This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Vadadustat is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor being investigated in the treatment of anemia secondary to chronic kidney disease.

Generic Name
Vadadustat
DrugBank Accession Number
DB12255
Background

One of the most common symptoms of advanced renal disease is anemia, caused primarily by the inability of the kidney to respond to anemic conditions with a corresponding increase in erythropoietin (EPO) production.4 Treatment of anemia of chronic kidney disease (CKD) has traditionally involved the administration of exogenous erythropoiesis-stimulating agents (ESAs), such as darbepoetin alfa, to counter the decrease in endogenous EPO production. While efficacious, the overuse of ESAs has been associated with cardiovascular complications, progression of CKD, and increases in overall mortality.4

A relatively new and alternative treatment option for patients with anemia of CKD are small molecule inhibitors of hypoxia-inducible factor prolyl-hydroxylase (HIF-PH). These agents inhibit prolyl-hydroxylase domain oxygen sensors, which essentially mimics hypoxic conditions and activates hypoxia-inducible factor, a transcription factor that serves a multitude of roles, including the stimulation erythropoiesis.4

Vadadustat is an orally administered inhibitor of hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) which is currently approved in Japan6 for the treatment for anemia due to CKD in both dialysis-dependent and non-dialysis dependent adult patients, and is currently awaiting a regulatory decision by the FDA for the same indication. The safety and efficacy of vadadustat have been shown to be non-inferior to darbepoetin alfa in patients with anemia of CKD undergoing dialysis,1,3 but it did not meet the prespecified noninferiority criterion for cardiovascular safety in a similar study in patients with non-dialysis-dependent CKD.2

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 306.7
Monoisotopic: 306.0407345
Chemical Formula
C14H11ClN2O4
Synonyms
  • Vadadustat
External IDs
  • Akb 6548
  • AKB-6548
  • B-506
  • B506
  • PG-1016548
  • PG1016548

Pharmacology

Indication

Not Available

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Hypoxia-inducible factors (HIFs) are transcription factors responsible for cellular survival under hypoxic conditions. They regulate a number of processes including angiogenesis, cell growth and differentiation, various metabolic processes, and erythropoiesis.4 Under normoxic conditions, HIF is degraded via hydroxylation by prolyl-hydroxylase domain (PHD) dioxygenases.

Vadadustat is an inhibitor of HIF-PHDs that facilitates increased HIF activity in the absence of hypoxic conditions.4 In patients with anemia of chronic kidney disease, in whom normal erythropoiesis is dysfunctional, this stimulates the production of erythropoietin and subsequent correction of anemia.

TargetActionsOrganism
AEgl nine homolog 1
inhibitor
Humans
AEgl nine homolog 2
inhibitor
Humans
AEgl nine homolog 3
inhibitor
Humans
UHypoxia-inducible factor 1-alpha
stabilization
Humans
UEndothelial PAS domain-containing protein 1
stabilization
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
N-acyl-alpha amino acids
Alternative Parents
Phenylpyridines / Pyridinecarboxylic acids and derivatives / 2-heteroaryl carboxamides / Chlorobenzenes / Hydroxypyridines / Aryl chlorides / Vinylogous acids / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds
show 7 more
Substituents
2-heteroaryl carboxamide / 3-phenylpyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
I60W9520VV
CAS number
1000025-07-9
InChI Key
JGRXMPYUTJLTKT-UHFFFAOYSA-N
InChI
InChI=1S/C14H11ClN2O4/c15-10-3-1-2-8(4-10)9-5-11(18)13(16-6-9)14(21)17-7-12(19)20/h1-6,18H,7H2,(H,17,21)(H,19,20)
IUPAC Name
2-{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]formamido}acetic acid
SMILES
OC(=O)CNC(=O)C1=C(O)C=C(C=N1)C1=CC(Cl)=CC=C1

References

General References
  1. Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, Farag YMK, Fishbane S, Hubert H, Jardine A, Khawaja Z, Koury MJ, Maroni BJ, Matsushita K, McCullough PA, Lewis EF, Luo W, Parfrey PS, Pergola P, Sarnak MJ, Spinowitz B, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Zwiech R, Chertow GM: Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Apr 29;384(17):1601-1612. doi: 10.1056/NEJMoa2025956. [Article]
  2. Chertow GM, Pergola PE, Farag YMK, Agarwal R, Arnold S, Bako G, Block GA, Burke S, Castillo FP, Jardine AG, Khawaja Z, Koury MJ, Lewis EF, Lin T, Luo W, Maroni BJ, Matsushita K, McCullough PA, Parfrey PS, Roy-Chaudhury P, Sarnak MJ, Sharma A, Spinowitz B, Tseng C, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Eckardt KU: Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD. N Engl J Med. 2021 Apr 29;384(17):1589-1600. doi: 10.1056/NEJMoa2035938. [Article]
  3. Nangaku M, Kondo K, Ueta K, Kokado Y, Kaneko G, Matsuda H, Kawaguchi Y, Komatsu Y: Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant. 2021 Aug 27;36(9):1731-1741. doi: 10.1093/ndt/gfab055. [Article]
  4. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
  5. BioPharma Dive: 5 FDA approval decisions to watch in the first quarter (2022) [Link]
  6. Akebia Therapeutics Press Release: Akebia Therapeutics Announces Top-Line Results from its PRO2TECT Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients Not on Dialysis [Link]
PubChem Compound
23634441
PubChem Substance
347828530
ChemSpider
34958379
BindingDB
107704
ChEMBL
CHEMBL3646221
ZINC
ZINC000117532869
PDBe Ligand
A1Z
Wikipedia
Vadadustat
PDB Entries
5opc / 5ox6

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAnemia1
3Active Not RecruitingTreatmentAnemia Associated With Chronic Kidney Disease (CKD)1
3CompletedOtherHealthy Subjects (HS)1
3CompletedTreatmentAnemia in Subjects With DD-CKD1
3CompletedTreatmentAnemia; Non-dialysis Dependent Chronic Kidney Disease1
3CompletedTreatmentAnemia; Peritoneal Dialysis Dependent Chronic Kidney Disease1
3CompletedTreatmentAnemia / Hemodialysis-dependent chronic kidney disease (HDD-CKD)1
3CompletedTreatmentAnemia / Non-dialysis Dependent Chronic Kidney Disease2
3CompletedTreatmentIron Deficiency Anemia caused by hemodialysis-dependent chronic kidney disease (HDD-CKD)2
3RecruitingTreatmentAnemia of Chronic Kidney Disease2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0436 mg/mLALOGPS
logP2.53ALOGPS
logP2.2ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)3.12ChemAxon
pKa (Strongest Basic)1.15ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area99.52 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity75.51 m3·mol-1ChemAxon
Polarizability29.63 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN1
Uniprot ID
Q9GZT9
Uniprot Name
Egl nine homolog 1
Molecular Weight
46020.585 Da
References
  1. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline 4-dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN2
Uniprot ID
Q96KS0
Uniprot Name
Egl nine homolog 2
Molecular Weight
43650.03 Da
References
  1. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Peptidyl-proline 4-dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific prol...
Gene Name
EGLN3
Uniprot ID
Q9H6Z9
Uniprot Name
Egl nine homolog 3
Molecular Weight
27261.06 Da
References
  1. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Stabilization
General Function
Ubiquitin protein ligase binding
Specific Function
Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transp...
Gene Name
HIF1A
Uniprot ID
Q16665
Uniprot Name
Hypoxia-inducible factor 1-alpha
Molecular Weight
92669.595 Da
References
  1. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Stabilization
General Function
Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity).
Specific Function
Dna binding
Gene Name
EPAS1
Uniprot ID
Q99814
Uniprot Name
Endothelial PAS domain-containing protein 1
Molecular Weight
96458.235 Da
References
  1. Sanghani NS, Haase VH: Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004. [Article]

Drug created at October 20, 2016 21:44 / Updated at January 08, 2022 03:27