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
Structure for Vadadustat (DB12255)
- 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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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.
Target Actions Organism AEgl nine homolog 1 inhibitorHumans AEgl nine homolog 2 inhibitorHumans AEgl nine homolog 3 inhibitorHumans UHypoxia-inducible factor 1-alpha stabilizationHumans UEndothelial PAS domain-containing protein 1 stabilizationHumans - 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- 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
- ATC Codes
- B03XA08 — Vadadustat
- 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
- 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]
- 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]
- 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]
- 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]
- BioPharma Dive: 5 FDA approval decisions to watch in the first quarter (2022) [Link]
- 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]
- External Links
- PubChem Compound
- 23634441
- PubChem Substance
- 347828530
- ChemSpider
- 34958379
- BindingDB
- 107704
- ChEMBL
- CHEMBL3646221
- ZINC
- ZINC000117532869
- PDBe Ligand
- A1Z
- Wikipedia
- Vadadustat
- PDB Entries
- 5opc / 5ox6 / 7ump
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Anemia Associated With Chronic Kidney Disease (CKD) 1 3 Completed Other Healthy Subjects (HS) 1 3 Completed Treatment Anemia 1 3 Completed Treatment Anemia; Non-dialysis Dependent Chronic Kidney Disease 1 3 Completed Treatment Anemia; Peritoneal Dialysis Dependent Chronic Kidney Disease 1 3 Completed Treatment Anemia / Dialysis Dependent Chronic Kidney Disease 2 3 Completed Treatment Anemia / Non-dialysis Dependent Chronic Kidney Disease 2 3 Completed Treatment Iron Deficiency Anemia caused by hemodialysis-dependent chronic kidney disease (HDD-CKD) 2 3 Suspended Treatment Anemia of Chronic Kidney Disease 2 3 Withdrawn Treatment Anemia / Dialysis Dependent Chronic Kidney Disease 1
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
Property Value Source Water Solubility 0.0436 mg/mL ALOGPS logP 2.53 ALOGPS logP 2.2 ChemAxon logS -3.8 ALOGPS pKa (Strongest Acidic) 3.12 ChemAxon pKa (Strongest Basic) 1.15 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 99.52 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 75.51 m3·mol-1 ChemAxon Polarizability 29.63 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
- 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
- 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
- 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
- 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
- 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
- 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