Details
Stereochemistry | ACHIRAL |
Molecular Formula | C19H16N6O4S |
Molecular Weight | 424.433 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=NC(C)=CN=C1NS(=O)(=O)C2=C(N=CC=C2)C3=CC=C(C=C3)C4=NN=CO4
InChI
InChIKey=FJHHZXWJVIEFGJ-UHFFFAOYSA-N
InChI=1S/C19H16N6O4S/c1-12-10-21-17(19(23-12)28-2)25-30(26,27)15-4-3-9-20-16(15)13-5-7-14(8-6-13)18-24-22-11-29-18/h3-11H,1-2H3,(H,21,25)
DescriptionSources: http://adisinsight.springer.com/drugs/800009560Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/15956965 | https://www.ncbi.nlm.nih.gov/pubmed/19065106
Sources: http://adisinsight.springer.com/drugs/800009560
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/15956965 | https://www.ncbi.nlm.nih.gov/pubmed/19065106
Zibotentan (ZD4054) is a potent and specific orally available endothelin A (ETA) receptor antagonist, with no measurable affinity for endothelin B receptor. Activation of the ETA receptor by ET-1 has emerged as an important factor promoting tumor cell proliferation, survival, angiogenesis, migration, invasion, and metastasis in several tumor types. Zibotentan inhibits endothelin-mediated mechanisms that promote tumour cell proliferation. Zibotentan was being developed by AstraZeneca as treatment for heart failure, hormone resistant prostate cancer and other cancers including non-small cell lung, ovarian and breast cancer. However, following disappointing results from a phase III trial in patients with advanced prostate cancer, AstraZeneca decided to discontinue the development of zibotentan as a potential treatment for cancer. AstraZeneca undertook preclinical studies in the UK with zibotentan to investigate its potential as a treatment for heart failure. However, development for this indication has been discontinued.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL252 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956965 |
8.27 null [pIC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
22.5 mg 1 times / day multiple, oral Highest studied dose Dose: 22.5 mg, 1 times / day Route: oral Route: multiple Dose: 22.5 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
DLT: Peripheral edema, Intraventricular hemorrhage... Dose limiting toxicities: Peripheral edema (grade 3, 33.3%) Sources: Page: p.5Intraventricular hemorrhage (grade 3, 33.3%) Headache (grade 3, 33.3%) Dyspnea (grade 3, 33.3%) |
15 mg 1 times / day multiple, oral Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 10 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 10 Sources: Page: p.5 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Dyspnea | grade 3, 33.3% DLT, Disc. AE |
22.5 mg 1 times / day multiple, oral Highest studied dose Dose: 22.5 mg, 1 times / day Route: oral Route: multiple Dose: 22.5 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
Headache | grade 3, 33.3% DLT, Disc. AE |
22.5 mg 1 times / day multiple, oral Highest studied dose Dose: 22.5 mg, 1 times / day Route: oral Route: multiple Dose: 22.5 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
Intraventricular hemorrhage | grade 3, 33.3% DLT, Disc. AE |
22.5 mg 1 times / day multiple, oral Highest studied dose Dose: 22.5 mg, 1 times / day Route: oral Route: multiple Dose: 22.5 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
Peripheral edema | grade 3, 33.3% DLT, Disc. AE |
22.5 mg 1 times / day multiple, oral Highest studied dose Dose: 22.5 mg, 1 times / day Route: oral Route: multiple Dose: 22.5 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 3 Sources: Page: p.5 |
PubMed
Title | Date | PubMed |
---|---|---|
Critical appraisal of cabazitaxel in the management of advanced prostate cancer. | 2010 Dec 3 |
|
Zibotentan for the treatment of castrate-resistant prostate cancer. | 2010 Jul |
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Update on castrate-resistant prostate cancer: 2010. | 2010 May |
|
Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer. | 2010 Nov |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19763400
Patients with metastatic, castrate-resistant prostate cancer (CRPC) were treated with escalating doses of oral zibotentan (ZD4054) 10-200 mg once daily. The maximum well-tolerated dose was 15 mg orally daily.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17620430
In the human ovarian cancer ET(A)R-positive cell lines HEY, OVCA 433, SKOV-3, and A-2780, 1 uM Zibotentan (ZD4054) effectively inhibited the basal and ET-1-induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins.
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CHEMBL1628688
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8054MM4902
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DB06629
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8664
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m11590
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186497-07-4
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SUB32097
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ZIBOTENTAN
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DTXSID70870171
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9910224
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100000124399
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C511404
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C48430
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UU-90
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ACTIVE MOIETY