ZIBOTENTAN

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

Structure Search

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)

HIDE SMILES / InChI

Description
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
Endothelin receptor ET-A 19 Target ID: CHEMBL252 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956965	Antagonist 2778		8.27 null [pIC50]

Conditions

Condition	Modality	Highest Phase	Product
Prostate cancer 178 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase III 656	Unknown Approved Use Unknown
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1132	Unknown Approved Use Unknown
Heart failure 103 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Preclinical	Unknown Approved Use Unknown

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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 Page: p.5	DLT: Peripheral edema, Intraventricular hemorrhage... Dose limiting toxicities: Peripheral edema (grade 3, 33.3%) Intraventricular hemorrhage (grade 3, 33.3%) Headache (grade 3, 33.3%) Dyspnea (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19763400 Page: p.5
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: https://pubmed.ncbi.nlm.nih.gov/19763400 Page: p.5	unhealthy, ADULT n = 10 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/19763400 Page: p.5	Sources: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 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: https://pubmed.ncbi.nlm.nih.gov/19763400 Page: p.5

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00AC2R	https://www.1pchem.com/search?query=1P00AC2R
AChemBlock	P50897	http://www.achemblock.com/catalogsearch/result/?q=P50897
AK Scientific	X7520	https://aksci.com/item_detail.php?cat=X7520
ApexBio Technology	A5489	https://www.apexbt.com/catalogsearch/result/?q=A5489
AstaTech	H11009	http://astatechinc.com/CPSResult.php?CRNO=H11009
BOC Sciences	186497-07-4	http://www.bocsci.com/description.asp?cas=186497-07-4
Chem Scene	CS-0492	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0492
ChemShuttle	151443	https://www.chemshuttle.com/catalogsearch/result/?q=151443
Hairui	HR144467	http://www.hairuichem.com/en/product/search.do?q=HR144467
KeyOrganics	AS-57168	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-57168
Lab Seeker	SC-71677	http://www.labseeker.com/search.php?keywords=SC-71677&category=0
LabSeeker	SC-71677	http://www.labseeker.com/search.php?keywords=SC-71677&category=0
MedChem Express	HY-10088	https://www.medchemexpress.com/search.html?q=HY-10088&ft=&fa=&fp=
MolPort	MolPort-005-943-325	https://www.molport.com/shop/molecule-link/MolPort-005-943-325
Molnova	M12880	https://www.molnova.com/en/serch-list.html?keywords=M12880
ShangHai Biochempartner	BCP02389	http://www.biochempartner.com/search_BCP02389
TargetMol	T6258	https://www.targetmol.com/search?keyword=T6258
Toronto Research Chemicals	E935003	https://www.trc-canada.com/product-detail/?CatNum=E935003
Toronto Research Chemicals	Z359900	https://www.trc-canada.com/product-detail/?CatNum=Z359900
eMolecules	32176607	https://orderbb.emolecules.com/search/#?query=32176607
eNovation Chemicals	D586669	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D586669&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-9265302849	https://mcule.com/MCULE-9265302849/

PubMed

Title	Date	PubMed
Emerging therapies in castrate-resistant prostate cancer.	2009 May	19363343
Critical appraisal of cabazitaxel in the management of advanced prostate cancer.	2010 Dec 3	21152241
An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers.	2010 Jul	20678684
Gateways to clinical trials.	2010 Nov	21225019
Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.	2010 Nov	20979929
Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial.	2010 Oct	20840318
ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole.	2010 Sep	19943105

Patents

Sample Use Guides

In Vivo Use Guide

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

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.

Name

Type

Language

ZIBOTENTAN

Official Name

English

N-(3-METHOXY-5-METHYLPYRAZIN-2-YL)-2-(4-(1,3,4-OXADIAZOL-2-YL)PHENYL)PRIDINE-3-SULFONAMIDE

Common Name

English

Zibotentan [WHO-DD]

Common Name

English

3-PYRIDINESULFONAMIDE, N-(3-METHOXY-5-METHYL-2-PYRAZINYL)-2-(4-(1,3,4-OXADIAZOL-2-YL)PHENYL)-

Systematic Name

English

ZIBOTENTAN [JAN]

Common Name

English

ZD4054

Code

English

N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide

Systematic Name

English

ZD-4054

Code

English

ZIBOTENTAN [USAN]

Common Name

English

ZIBOTENTAN [MART.]

Common Name

English

zibotentan [INN]

Common Name

English

ZIBOTENTAN [MI]

Common Name

English

Code System Code Type Description

ChEMBL

CHEMBL1628688