ZIBOTENTAN

Investigational

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=CC=CN=C2C3=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

Molecular Formula	C19H16N6O4S
Molecular Weight	424.433
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 22 Target ID: CHEMBL252 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956965	Antagonist 2849		8.27 null [pIC50]

Conditions

Condition	Modality	Highest Phase	Product
Prostate cancer 186 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase III 665	Unknown Approved Use Unknown
Breast cancer 432 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1147	Unknown Approved Use Unknown
Colorectal cancer 102 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1147	Unknown Approved Use Unknown
Ovarian cancer 160 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1147	Unknown Approved Use Unknown
Non-small cell lung cancer 211 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Phase II 1147	Unknown Approved Use Unknown
Heart failure 106 Sources: http://adisinsight.springer.com/drugs/800009560	Primary	Preclinical	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
566 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21414193/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1165.07 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19763400	22.5 mg single, oral dose: 22.5 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
5480 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21414193/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12298 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19763400	22.5 mg single, oral dose: 22.5 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
9.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21414193/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.24 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19763400	22.5 mg single, oral dose: 22.5 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
22.5% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21414193/	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ZIBOTENTAN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: 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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400	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
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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400	Sources: https://pubmed.ncbi.nlm.nih.gov/19763400

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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400
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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400
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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400
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	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/19763400

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
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
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
mcule	MCULE-9265302849	https://mcule.com/MCULE-9265302849/
MedChem Express	HY-10088	https://www.medchemexpress.com/search.html?q=HY-10088&ft=&fa=&fp=
Molnova	M12880	https://www.molnova.com/en/serch-list.html?keywords=M12880
MolPort	MolPort-005-943-325	https://www.molport.com/shop/molecule-link/MolPort-005-943-325
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

PubMed

Title	Date	PubMed
Critical appraisal of cabazitaxel in the management of advanced prostate cancer.	2010-12-03	21152241
Gateways to clinical trials.	2010-11	21225019
Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.	2010-11	20979929
Docetaxel-based combination therapy for castration-resistant prostate cancer.	2010-11	20351071
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.	2010-10	20840318
ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole.	2010-09	19943105
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.	2010-07	20678684
Zibotentan for the treatment of castrate-resistant prostate cancer.	2010-07	20497097
Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancer.	2010-06	20628434
Update on castrate-resistant prostate cancer: 2010.	2010-05	20177381
Emerging therapies in castrate-resistant prostate cancer.	2009-05	19363343
Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence.	2005-06-20	15956965

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.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:15:27 GMT 2025` Edited by `admin` on `Mon Mar 31 18:15:27 GMT 2025`
Record UNII	8054MM4902
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ZIBOTENTAN

Official Name

English

ZD-4054

Preferred 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

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