Details
Stereochemistry | ACHIRAL |
Molecular Formula | C19H27N3O6 |
Molecular Weight | 393.4342 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)CNC(=O)C1C(=O)N(C2CCCCC2)C(=O)N(C3CCCCC3)C1=O
InChI
InChIKey=RUEYEZADQJCKGV-UHFFFAOYSA-N
InChI=1S/C19H27N3O6/c23-14(24)11-20-16(25)15-17(26)21(12-7-3-1-4-8-12)19(28)22(18(15)27)13-9-5-2-6-10-13/h12-13,15H,1-11H2,(H,20,25)(H,23,24)
Molecular Formula | C19H27N3O6 |
Molecular Weight | 393.4342 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/28242135Curator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/28928122 | https://www.ncbi.nlm.nih.gov/pubmed/27978511
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28242135
Curator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/28928122 | https://www.ncbi.nlm.nih.gov/pubmed/27978511
Daprodustat (GSK1278863) is a low nanomolar hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor, that increases HIF stability and action. In preclinical studies, Daprodustat stabilizes HIFα in cell lines, resulting in the production of increased levels of erythropoietin (EPO). In normal mice, a single dose of Daprodustat induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. Daprodustat significantly increased reticulocytes and red cell mass parameters in pre-clinical species following once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile supporting continued clinical development. In a phase 1 study, Daprodustat was well tolerated and increased erythropoietin (EPO) levels in apparently healthy individuals proportional to dose. In phase 2a studies in non–dialysis-dependent chronic kidney disease (NDD CKD) and end-stage renal disease Daprodustat 4-10 mg once-daily produced the dose-dependent increase in hemoglobin relative to placebo. The Phase III programme for the drug includes two studies evaluating its safety and efficacy compared to recombinant human erythropoietin in dialysis-dependent subjects with anemia associated with CKD (ASCEND-D) and in non-dialysis dependent patients with the condition (ASCEND-ND).
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3028 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28928122 |
3.5 nM [IC50] | ||
Target ID: CHEMBL5697 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28928122 |
22.2 nM [IC50] | ||
Target ID: CHEMBL5705 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28928122 |
5.5 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 71.0 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2020/P20200619003/340278000_30200AMX00505_I100_1.pdf#page=53 Page: 53.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2020/P20200619003/340278000_30200AMX00505_I100_1.pdf#page=53 Page: 53.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2020/P20200619003/340278000_30200AMX00505_I100_1.pdf#page=53 Page: 53.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 70.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
yes [IC50 11 uM] | |||
Page: 70.0 |
yes [IC50 21 uM] | |||
Page: 71.0 |
yes [IC50 6 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 71.0 |
major | yes (co-administration study) Comment: Gemfibrozil increased Cmax and AUCinf by 3.9-fold and 18.6-fold. Page: 71.0 |
||
Page: 71.0 |
minor | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
no | ||||
Page: 71.0 |
no | |||
Page: 71.0 |
no | |||
Page: 71.0 |
weak | |||
Page: 71.0 |
weak | |||
Page: 71.0 |
yes | |||
Page: 71.0 |
yes | |||
Page: 71.0 |
yes | |||
Page: 71.0 |
yes | |||
Page: 71.0 |
yes | |||
Page: 71.0 |
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28242135
0.5, 2, and 5 mg once-daily for 4-week treatment
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28928122
Human CP4H/Cofactor mix (4X final concentration in 50 mM HEPES, pH 7.5 with 50 mM KCl) was incubated at room temperature for 30 minutes with GSK1278863 (10 point, 3-fold serial dilution in 50% DMSO, 15X final concentration) or 50% DMSO. Substrate mix (1.4X final concentration in 50 mM HEPES, pH 7.5 with 50 mM KCl) was added to the plate yielding a 32 μL final reaction volume. After 20 minutes, the reaction was quenched by the addition of 0.67% final H3PO4. Product formation was detected using Reverse Phase High Performance Liquid Chromatography (HPLC; Ex 336nM and Em 517 nM). Final concentrations of the CP4H/Cofactor mix were 21.11 nM enzyme, 1 mg/mL BSA, 50 μM FeCl2, 2 mM ascorbic acid, 100 μM DTT, and 100 μg/mL catalase. The substrate mix consisted of 100 μM dansyl-GFPG-Oet, and 110 μM α-ketoglutarate. Percent inhibition data were determined from the ratio of product to substrate after a 20 minute reaction. The IC50 value was determined by fitting the percent inhibition data to a two-parameter IC50 equation.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 16:54:58 GMT 2023
by
admin
on
Sat Dec 16 16:54:58 GMT 2023
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Record UNII |
JVR38ZM64B
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Record Status |
Validated (UNII)
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Record Version |
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-
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Code System | Code | Type | Description | ||
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Daprodustat
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JVR38ZM64B
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DB11682
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JVR38ZM64B
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DTXSID501337360
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SUB185070
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BC-163
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91617630
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10167
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C169877
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960539-70-2
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CHEMBL3544988
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100000170880
Created by
admin on Sat Dec 16 16:54:58 GMT 2023 , Edited by admin on Sat Dec 16 16:54:58 GMT 2023
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