PAZOPANIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H23N7O2S
Molecular Weight	437.518
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN(C1=CC2=NN(C)C(C)=C2C=C1)C3=CC=NC(NC4=CC=C(C)C(=C4)S(N)(=O)=O)=N3

InChI

InChIKey=CUIHSIWYWATEQL-UHFFFAOYSA-N

InChI=1S/C21H23N7O2S/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25)

HIDE SMILES / InChI

Molecular Formula	C21H23N7O2S
Molecular Weight	437.518
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

Pazopanib (VOTRIENT) is an orally bioavailable multi-targeted tyrosine kinase receptor inhibitor. Pazopanib inhibits vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR) -1 and -3, cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). In an vitro study, pazopanib exerted anti-tumor effect through mechanisms including the Raf-MAPK/ERK (MEK)-extracellular signal-regulated kinase (ERK) pathway. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Pazopanib (VOTRIENT) was developed by GlaxoSmithKline for the treatment of solid tumours and age-related macular degeneration. However, Novartis acquired all the rights to the drug from GlaxoSmithKline. Pazopanib (VOTRIENT) is indicated for the treatment of patients with advanced renal cell carcinoma and advanced soft tissue sarcoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Fibroblast growth factor receptor 1 45	Inhibitor 8,297	0.14 µM [IC50]
Fibroblast growth factor receptor 3 32	Inhibitor 8,297	0.13 µM [IC50]
Macrophage colony stimulating factor receptor 24	Inhibitor 8,297	0.146 µM [IC50]
Platelet-derived growth factor receptor alpha 30	Inhibitor 8,297	0.071 µM [IC50]
Platelet-derived growth factor receptor beta 56	Inhibitor 8,297	0.084 µM [IC50]
Stem cell growth factor receptor 53	Inhibitor 8,297	0.074 µM [IC50]
Tyrosine-protein kinase ITK/TSK 4	Inhibitor 8,297	0.43 µM [IC50]
Tyrosine-protein kinase LCK 12	Inhibitor 8,297	0.411 µM [IC50]
Vascular endothelial growth factor receptor 1 41	Inhibitor 8,297	0.01 µM [IC50]
Vascular endothelial growth factor receptor 2 104	Inhibitor 8,297	0.03 µM [IC50]
Vascular endothelial growth factor receptor 3 41	Inhibitor 8,297	0.047 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Renal cell carcinoma 31	Primary		Approved 8,429	VOTRIENT
Soft tissue sarcoma 10	Primary		Approved 8,429	VOTRIENT

C_max

Value	Dose	Analyte	Population
44.8 mg/L	800 mg 1 times / day multiple, oral	PAZOPANIB blood	Homo sapiens
50.2 mg/L	600 mg 1 times / day multiple, oral	PAZOPANIB blood	Homo sapiens
58.1 μg/mL	800 mg single, oral	PAZOPANIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
821 mg × h/L	800 mg 1 times / day multiple, oral	PAZOPANIB blood	Homo sapiens
895 mg × h/L	600 mg 1 times / day multiple, oral	PAZOPANIB blood	Homo sapiens
1037 μg × h/mL	800 mg single, oral	PAZOPANIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%			PAZOPANIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290	Disc. AE: Proteinuria...
800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290	Disc. AE: ALT increased, AST increased...
600 mg 1 times / day multiple, oral MTD	unhealthy, 61 years (range: 38–76 years) n = 8	DLT: Neutropenia, Aspartate aminotransferase increased... Other AEs: Diarrhea, Hypertension...
800 mg 1 times / day multiple, oral	unhealthy, 61 years (range: 38–76 years) n = 5	DLT: Aspartate aminotransferase increase, Malaise...
800 mg 1 times / day multiple, oral Recommended	unhealthy, adult	Other AEs: Hepatotoxicity...

Showing 1 to 5 of 7 entries

Previous1 2Next

AEs

Show entries

AE	Significance	Dose	Population
Proteinuria	5 patients Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290
Fatigue	10 patients Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290
ALT increased	11 patient Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290
AST increased	11 patient Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290
Bilirubin increased	11 patient Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, 59 years n = 290

Showing 1 to 5 of 58 entries

Previous1 2 3 4 5…12Next

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 P-gp 1,461 UGT1A1 204 OATP1B1 788	CYP1A2 1,054 CYP2C8 693 P-gp 1,537	CYP2B6 547 CYP1A2 701

Drug as perpetrator

Show entries

Target	Modality	Activity	Clinical evidence
CYP2C8 965	inhibitor 3,277	moderate [IC50 10 uM]	weak (co-administration study)
CYP2C19 1,553	inhibitor 3,277	moderate [IC50 11 uM]	no (co-administration study)
CYP3A4 1,925	inhibitor 3,277	moderate [IC50 11 uM]	weak (co-administration study)
CYP2B6 1,001	inhibitor 3,277	moderate [IC50 15 uM]
CYP1A2 1,692	inhibitor 3,277	moderate [IC50 16 uM]	no (co-administration study)

Showing 1 to 5 of 14 entries

Previous1 2 3Next

Drug as victim

Show entries

Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	minor
CYP2C8 693	substrate 3,367	minor
P-gp 1,537	substrate 3,367	yes	yes (co-administration study)

Showing 1 to 4 of 4 entries

Previous1Next

Tox targets

Show entries

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

Showing 1 to 1 of 1 entries

Previous1Next

Sourcing

Sourcing

Show entries

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:71219	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:71219
MolPort	MolPort-006-827-156	https://www.molport.com/shop/molecule-link/MolPort-006-827-156
Selleck Chemicals	pazopanib	http://www.selleckchem.com/products/pazopanib.html
ZINC	ZINC000011617039	http://zinc15.docking.org/substances/ZINC000011617039
eMolecules	30151586	https://www.emolecules.com/cgi-bin/more?vid=30151586

Showing 1 to 5 of 5 entries

Previous1Next

PubMed

Show entries

Title	Date	PubMed
Recent advances in the therapy of renal cancer.	2007 Feb	17250461
Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity.	2007 Jul	17620431
Neovascular age-related macular degeneration: potential therapies.	2008	18484796
New drugs for ovarian cancer.	2008 Feb	18347558
Update on novel therapeutic agents for cervical cancer.	2008 Sep	18544460

Showing 1 to 5 of 34 entries

Previous1 2 3 4 5 6 7Next

Patents

Sample Use Guides

In Vivo Use Guide

800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). Baseline moderate hepatic impairment – 200 mg orally once daily. Not recommended in patients with severe hepatic impairment.

Route of Administration: Oral

In Vitro Use Guide

Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 uM, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects

Substance Class	Chemical
Record UNII	7RN5DR86CK
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

PAZOPANIB

Official Name

English

PAZOPANIB [VANDF]

Common Name

English

PAZOPANIB [EMA EPAR]

Common Name

English

5-((4-((2,3-DIMETHYL-2H-INDAZOL-6-YL)(METHYL)AMINO)PYRIMIDIN-2-YL)AMINO)-2-METHYLBENZENESULFONAMIDE

Systematic Name

English

GW786034

Code

English

Showing 1 to 5 of 10 entries

Previous1 2Next

Show entries

Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

705819

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

KIDNEY NEOPLASMS

EMA ASSESSMENT REPORTS

VOTRIENT (AUTHORIZED: CARCINOMA, RENAL CELL)

Designated/Withdrawn

FDA ORPHAN DRUG

383912

Protein kinase inhibitors

WHO-ATC

L01XE11

Showing 1 to 5 of 10 entries

Previous1 2Next

Show entries

Code System

Code

Type

Description

EVMPD

SUB29175

PRIMARY

ChEMBL

CHEMBL477772

PRIMARY

PUBCHEM

10113978

PRIMARY

NDF-RT

N0000182137

PRIMARY

Cytochrome P450 2D6 Inhibitors [MoA]

HSDB

8210

PRIMARY

Showing 1 to 5 of 24 entries

Previous1 2 3 4 5Next

Show entries

Related Record

Type

Details


					AIN96D6SGL

OATP1B1

TRANSPORTER -> SUBSTRATE


					HH55AX8FNP

PAZOPANIB HYDROCHLORIDE MONOHYDRATE

SALT/SOLVATE -> PARENT

Amount:


					798536Z7S0

VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2

TARGET -> INHIBITOR


					33Y9ANM545

PAZOPANIB HYDROCHLORIDE

SALT/SOLVATE -> PARENT

Amount:

Showing 1 to 4 of 4 entries

Previous1Next

Show entries

Related Record

Type

Details


					SX3LHF7K66

GSK-1268992

METABOLITE INACTIVE -> PARENT

Comments:

LESS THAN 10%

Qualification:

PLASMA

Amount:

RELATIONSHIP_AMOUNT [<10] (limits)


					Z51V93OIDV

GSK-1071306

METABOLITE INACTIVE -> PARENT

Comments:

In plasma and blood, individual circulating metabolites represented less than 10% total radioactivity

Qualification:

PLASMA

Amount:

RELATIONSHIP_AMOUNT [<10] (limits)


					23M9H61WO8

GSK-1268997

METABOLITE ACTIVE -> PARENT

Comments:

Only one of these metabolites (GSK1268997) has been shown to inhibit the proliferation of VEGF-stimulated human umbilical vein endothelial cells with potency similar to pazopanib. The other metabolites show at least 10- to 20-fold less activity than the parent compound in the same cellular assay.


					SX3LHF7K66

GSK-1268992

METABOLITE INACTIVE -> PARENT

Qualification:

FECAL

Amount:

RELATIONSHIP_AMOUNT 6 MOLE PERCENT (average)


					23M9H61WO8

GSK-1268997

METABOLITE ACTIVE -> PARENT

Comments:

The majority of radiolabeled material recovered in feces constituted unchanged pazopanib, accounting for a mean of 67% of the administered radioactivity activity dose. Pazopanib metabolites GSK1268992 and GSK1268997 accounted for means of approximately 6% and 2% of the administered radioactivity dose, respectively.

Qualification:

FECAL

Amount:

RELATIONSHIP_AMOUNT 2 (average)

Showing 1 to 5 of 9 entries

Previous1 2Next

Show entries

Related Record

Type

Details


					7RN5DR86CK

PAZOPANIB

ACTIVE MOIETY

Showing 1 to 1 of 1 entries

Previous1Next

Name	Property Type	Amount	Referenced Substance	Defining	Parameters	References
Biological Half-life	PHARMACOKINETIC		`7RN5DR86CK` PAZOPANIB		Elimination PHARMACOKINETIC 31 hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

F_unbound

Drug as perpetrator