Page last updated: 2024-11-13

gsk1278863

Description Research Excerpts Clinical Trials Roles Classes Pathways Study Profile Bioassays Related Drugs Related Conditions Protein Interactions Research Growth Market Indicators

Description

GSK1278863: a HIF prolyl hydroxylase inhibitor [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

daprodustat : A member of the class of barbiturates that is barbituric acid substituted by cyclohexyl groups at positions 1 and 3, and by a (carboxymethyl)aminocarbonyl group at position 5. It is an inhibitor of hypoxia-inducible factor prolyl hydroxylase developed by GlaxoSmithKline for the treatment of anaemia in patients with chronic kidney disease. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Cross-References

ID SourceID
PubMed CID91617630
CHEMBL ID3544988
SCHEMBL ID21725048
MeSH IDM000608110

Synonyms (47)

Synonym
S8171
daprodustat [who-dd]
daprodustat [usan]
daprodustat [inn]
daprodustat [jan]
jesduvroq
n-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine
jvr38zm64b ,
daprodustat
gsk 1278863
gsk1278863
glycine, n-((1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl)-
unii-jvr38zm64b
daprodustat [usan:inn]
gsk-1278863
960539-70-2
n-((1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl)glycine
2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid
gtpl8455
duvroq
AC-30915
CHEMBL3544988
HY-17608
CS-5453
daprodustat; gsk1278863
EX-A1121
AKOS027439964
2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinan-5-yl)formamido]acetic acid
duvroq (tn)
D10874
daprodustat (jan/usan/inn)
A902761
DB11682
BCP16766
daprodustat (gsk1278863)
Q27076986
SB19761
AMY27907
CCG-268574
daprodustat;(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine
MS-26596
(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine
SCHEMBL21725048
BG166670
DTXSID501337360
daprodustatum
bdbm50606586

Research Excerpts

Overview

GSK1278863 is an orally administered small-molecule PHI. It is under investigation for treatment of anemia associated with chronic kidney disease.

ExcerptReferenceRelevance
"GSK1278863 is an investigative drug under investigation for treatment of anemia associated with chronic kidney disease. "( Overcoming bioanalytical challenges associated with the separation and quantitation of GSK1278863, a HIF-prolyl hydroxylase inhibitor, and its 14 stereoisomeric metabolites.
Evans, CA; Knecht, D; Licea Perez, H, 2016
)
2.1
"GSK1278863 is an orally administered small-molecule PHI."( A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial.
Brigandi, RA; Cross, N; de Zoysa, J; Guptha, V; Johnson, B; Kumar, S; McMahon, L; Oei, C; Olbina, G; Roger, SD; Russ, SF; Sahay, M; Singh, N; Smolyarchuk, EA; Westerman, M, 2016
)
1.4

Toxicity

ExcerptReferenceRelevance
" Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians."( Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.
Caltabiano, S; Hara, K; Takahashi, N; Wakamatsu, A, 2015
)
0.65
" Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa."( Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.
Akizawa, T; Cobitz, AR; Endo, Y; Hara, K; Kawamatsu, S; Nangaku, M; Okuda, N; Onoue, T; Yonekawa, T, 2020
)
0.56
" The most frequent adverse events included nasopharyngitis (29%), catheter-site infection (18%), peritonitis (16%), diarrhea (14%), and nausea (11%)."( Efficacy and safety of daprodustat in Japanese peritoneal dialysis patients.
Cobitz, A; Endo, Y; Kanai, H; Kurata, K; Nagai, R; Nagakubo, T; Nangaku, M; Okuda, N, 2021
)
0.62
" The incidence per 100 patient-years of on-therapy adverse events (AEs) was 363."( Safety of daprodustat in patients with anemia of chronic kidney disease: A pooled analysis of phase 3 studies in Japan.
Akizawa, T; Cobitz, A; Endo, Y; Kimura, T; Nagakubo, T; Nangaku, M; Yonekawa, T, 2022
)
0.72
" Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability."( Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.
Blackorby, A; Carroll, K; Cizman, B; Cobitz, AR; Jha, V; Johansen, KL; Lopes, RD; Macdougall, IC; McMurray, JJV; Meadowcroft, AM; Obrador, GT; Paul, G; Perkovic, V; Ranganathan, P; Sedani, S; Singh, AK; Solomon, S; Stankus, N; Strutz, F; Waikar, SS; Wanner, C; Wheeler, DC; Wiecek, A, 2022
)
0.72
" Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa."( Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.
Blackorby, A; Carroll, K; Cizman, B; Cobitz, AR; Jha, V; Johansen, KL; Lopes, RD; Macdougall, IC; McMurray, JJV; Meadowcroft, AM; Obrador, GT; Paul, G; Perkovic, V; Ranganathan, P; Sedani, S; Singh, AK; Solomon, S; Stankus, N; Strutz, F; Waikar, SS; Wanner, C; Wheeler, DC; Wiecek, A, 2022
)
0.72
"The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD."( Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.
Atkins, MB; Barker, T; Blackorby, A; Carroll, K; Claggett, BL; Cobitz, AR; DiMino, T; Mallett, S; McCausland, FR; McMurray, JJV; Meadowcroft, A; Perkovic, V; Singh, AK; Snapinn, S; Solomon, SD; Wanner, C; Wiecek, A; Wittes, J, 2023
)
0.91

Compound-Compound Interactions

ExcerptReferenceRelevance
"This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively."( The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects.
Caltabiano, S; Cizman, B; Cobitz, AR; Lister, K; Mahar, KM; Ravindranath, R; Tenero, D, 2018
)
0.48

Bioavailability

ExcerptReferenceRelevance
"Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease."( Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study.
Andrews, SM; Chattoraj, S; Cobitz, A; Israni, R; Mahar, KM; Shaddinger, B; Sprys, M, 2023
)
0.91

Dosage Studied

ExcerptRelevanceReference
"These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen."( A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis.
Bailey, CK; Caltabiano, S; Cobitz, AR; Huang, C; Mahar, KM; Patel, VV, 2019
)
0.51
"Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033."( Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial.
Bailey, CK; Cobitz, AR; Connaire, J; Coyne, DW; DiMino, TL; Huang, C; Kim, SG; Lopes, RD; Orias, M; Patel, V; Rastogi, A; Shah, S; Singh, AK; Wanner, C, 2022
)
0.72
" In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks)."( Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.
Atkins, MB; Barker, T; Blackorby, A; Carroll, K; Claggett, BL; Cobitz, AR; DiMino, T; Mallett, S; McCausland, FR; McMurray, JJV; Meadowcroft, A; Perkovic, V; Singh, AK; Snapinn, S; Solomon, SD; Wanner, C; Wiecek, A; Wittes, J, 2023
)
0.91
" Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat."( Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.
Atkins, MB; Barker, T; Blackorby, A; Carroll, K; Claggett, BL; Cobitz, AR; DiMino, T; Mallett, S; McCausland, FR; McMurray, JJV; Meadowcroft, A; Perkovic, V; Singh, AK; Snapinn, S; Solomon, SD; Wanner, C; Wiecek, A; Wittes, J, 2023
)
0.91
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Protein Targets (2)

Inhibition Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Egl nine homolog 1Homo sapiens (human)IC50 (µMol)0.06700.00701.86148.0000AID1916161
Hypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)IC50 (µMol)21.00008.60008.60008.6000AID1916162
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (20)

Processvia Protein(s)Taxonomy
response to hypoxiaEgl nine homolog 1Homo sapiens (human)
intracellular iron ion homeostasisEgl nine homolog 1Homo sapiens (human)
intracellular oxygen homeostasisEgl nine homolog 1Homo sapiens (human)
negative regulation of DNA-binding transcription factor activityEgl nine homolog 1Homo sapiens (human)
regulation of angiogenesisEgl nine homolog 1Homo sapiens (human)
positive regulation of transcription by RNA polymerase IIEgl nine homolog 1Homo sapiens (human)
negative regulation of cyclic-nucleotide phosphodiesterase activityEgl nine homolog 1Homo sapiens (human)
cardiac muscle tissue morphogenesisEgl nine homolog 1Homo sapiens (human)
heart trabecula formationEgl nine homolog 1Homo sapiens (human)
ventricular septum morphogenesisEgl nine homolog 1Homo sapiens (human)
labyrinthine layer developmentEgl nine homolog 1Homo sapiens (human)
response to nitric oxideEgl nine homolog 1Homo sapiens (human)
regulation of modification of postsynaptic structureEgl nine homolog 1Homo sapiens (human)
regulation protein catabolic process at postsynapseEgl nine homolog 1Homo sapiens (human)
peptidyl-proline hydroxylation to 4-hydroxy-L-prolineEgl nine homolog 1Homo sapiens (human)
cellular response to hypoxiaEgl nine homolog 1Homo sapiens (human)
positive regulation of myoblast differentiationHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
negative regulation of Notch signaling pathwayHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
negative regulation of DNA-templated transcriptionHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
positive regulation of vasculogenesisHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (19)

Processvia Protein(s)Taxonomy
protein bindingEgl nine homolog 1Homo sapiens (human)
ferrous iron bindingEgl nine homolog 1Homo sapiens (human)
2-oxoglutarate-dependent dioxygenase activityEgl nine homolog 1Homo sapiens (human)
enzyme bindingEgl nine homolog 1Homo sapiens (human)
L-ascorbic acid bindingEgl nine homolog 1Homo sapiens (human)
peptidyl-proline dioxygenase activityEgl nine homolog 1Homo sapiens (human)
hypoxia-inducible factor-proline dioxygenase activityEgl nine homolog 1Homo sapiens (human)
peptidyl-proline 4-dioxygenase activityEgl nine homolog 1Homo sapiens (human)
transcription corepressor activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
Notch bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
protein bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
ferrous iron bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
zinc ion bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
oxygen sensor activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
carboxylic acid bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
peptidyl-histidine dioxygenase activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
[protein]-asparagine 3-dioxygenase activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
protein homodimerization activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
NF-kappaB bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
peptidyl-aspartic acid 3-dioxygenase activityHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
ankyrin repeat bindingHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (8)

Processvia Protein(s)Taxonomy
cytoplasmEgl nine homolog 1Homo sapiens (human)
cytosolEgl nine homolog 1Homo sapiens (human)
postsynaptic densityEgl nine homolog 1Homo sapiens (human)
intracellular membrane-bounded organelleEgl nine homolog 1Homo sapiens (human)
glutamatergic synapseEgl nine homolog 1Homo sapiens (human)
nucleusEgl nine homolog 1Homo sapiens (human)
cytoplasmEgl nine homolog 1Homo sapiens (human)
nucleusHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
nucleoplasmHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
cytoplasmHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
cytosolHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
perinuclear region of cytoplasmHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
cytoplasmHypoxia-inducible factor 1-alpha inhibitorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (4)

Assay IDTitleYearJournalArticle
AID1916161Inhibition of N-terminal His tagged PHD2 (181 to 426 residues) (unknown origin) measured by MALDI-TOF MS analysis2021Journal of medicinal chemistry, 06-10, Volume: 64, Issue:11
Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy.
AID1495355Half life in patient administered as qd2018Bioorganic & medicinal chemistry letters, 06-01, Volume: 28, Issue:10
Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal anemia.
AID1916162Inhibition of FIH (unknown origin) by solid-phase extraction coupled to MS based assay2021Journal of medicinal chemistry, 06-10, Volume: 64, Issue:11
Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy.
AID1347411qHTS to identify inhibitors of the type 1 interferon - major histocompatibility complex class I in skeletal muscle: primary screen against the NCATS Mechanism Interrogation Plate v5.0 (MIPE) Libary2020ACS chemical biology, 07-17, Volume: 15, Issue:7
High-Throughput Screening to Identify Inhibitors of the Type I Interferon-Major Histocompatibility Complex Class I Pathway in Skeletal Muscle.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (62)

TimeframeStudies, This Drug (%)All Drugs %
pre-19900 (0.00)18.7374
1990's0 (0.00)18.2507
2000's0 (0.00)29.6817
2010's19 (30.65)24.3611
2020's43 (69.35)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 24.78

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be moderate demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index24.78 (24.57)
Research Supply Index4.43 (2.92)
Research Growth Index4.89 (4.65)
Search Engine Demand Index24.72 (26.88)
Search Engine Supply Index2.00 (0.95)

This Compound (24.78)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials21 (33.87%)5.53%
Reviews13 (20.97%)6.00%
Case Studies1 (1.61%)4.05%
Observational0 (0.00%)0.25%
Other27 (43.55%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]