SORAFENIB TOSYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H16ClF3N4O3.C7H8O3S
Molecular Weight	637.027
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC1=CC=C(C=C1)S(O)(=O)=O.CNC(=O)C2=NC=CC(OC3=CC=C(NC(=O)NC4=CC=C(Cl)C(=C4)C(F)(F)F)C=C3)=C2

InChI

InChIKey=IVDHYUQIDRJSTI-UHFFFAOYSA-N

InChI=1S/C21H16ClF3N4O3.C7H8O3S/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25;1-6-2-4-7(5-3-6)11(8,9)10/h2-11H,1H3,(H,26,30)(H2,28,29,31);2-5H,1H3,(H,8,9,10)

HIDE SMILES / InChI

Description

Sorafenib (BAY 43-9006), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer, hepatocellular carcinoma and for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials. Sorafenib was shown to interact with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, VEGFR- 2, VEGFR- 3, and PDGFR- ß). Several of these kinases are thought to be involved in angiogenesis. Thus, sorafenib may inhibit tumor growth by a dual mechanism, acting either directly on the tumor (through inhibition of Raf and Kit signaling) and/or on tumor angiogenesis (through inhibition of VEGFR and PDGFR signaling). Sorafenib inhibited tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis was seen in some tumor xenograft models.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase B-raf 21	Inhibitor 8,504
Serine/threonine-protein kinase RAF 11	Inhibitor 8,504
Vascular endothelial growth factor receptor 11	Inhibitor 8,504
Tyrosine-protein kinase receptor FLT3 42	Inhibitor 8,504
Platelet-derived growth factor receptor beta 56	Inhibitor 8,504
Stem cell growth factor receptor 57	Inhibitor 8,504
Tyrosine-protein kinase receptor RET 16	Inhibitor 8,504	50.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hepatocellular carcinoma 83	Primary	Approved 8,583	NEXAVAR
Differentiated thyroid carcinoma 2	Primary	Approved 8,583	NEXAVAR
Renal cell carcinoma 33	Primary	Approved 8,583	NEXAVAR

C_max

Value	Dose	Analyte	Population
9.35 μg/mL	400 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
2.31 μg/mL	100 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
9.81 μg/mL	600 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
7.21 μg/mL	800 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
2.44 μg/mL	400 mg single, oral	SORAFENIB plasma	Homo sapiens
3.42 μg/mL	400 mg single, oral	SORAFENIB plasma	Homo sapiens
1.98 μg/mL	100 mg single, oral	SORAFENIB plasma	Homo sapiens
2.69 μg/mL	100 mg single, oral	SORAFENIB plasma	Homo sapiens
3.1 μg/mL	600 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
3.8 μg/mL	400 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
0.43 mg/L	100 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
71.7 mg × h/L	400 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
23.8 mg × h/L	100 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
79 mg × h/L	600 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
44.9 mg × h/L	800 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
82.3 mg × h/L	400 mg single, oral	SORAFENIB plasma	Homo sapiens
106.98 mg × h/L	400 mg single, oral	SORAFENIB plasma	Homo sapiens
49.8 mg × h/L	100 mg single, oral	SORAFENIB plasma	Homo sapiens
83.8 mg × h/L	100 mg single, oral	SORAFENIB plasma	Homo sapiens
12.6 μg × h/mL	600 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
17.9 μg × h/mL	400 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens
9.4 mg × h/L	100 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
28.1 h	400 mg single, oral	SORAFENIB plasma	Homo sapiens
23.8 h	400 mg single, oral	SORAFENIB plasma	Homo sapiens
37.9 h	100 mg single, oral	SORAFENIB plasma	Homo sapiens
28.9 h	100 mg single, oral	SORAFENIB plasma	Homo sapiens
27.1 h	100 mg 2 times / day multiple, oral	SORAFENIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.31%	600 mg 2 times / day multiple, oral		SORAFENIB plasma	Homo sapiens
0.29%	400 mg 2 times / day multiple, oral		SORAFENIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years	DLT: Hypertension, Rash... Other AEs: Dyspnea, Rash...
600 mg 2 times / day multiple, oral MTD	unhealthy, Mean age 53.7 years	Other AEs: Ascites, Constipation...
800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Median age 57 years	Other AEs: Diarrhea...
800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Median age 57 years	Other AEs: Hand and foot skin reaction, Desquamation...
400 mg 2 times / day multiple, oral Recommended	unhealthy, Median age 58 years	Other AEs: Hypertension, Fatigue...

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AEs

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AE	Significance	Dose	Population
Anorexia	grade 1, 33%	800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years
Nausea	grade 1, 33%	800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years
Pharyngitis	grade 1, 33%	800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years
Fatigue	grade 1, 67%	800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years
Pruritis	grade 1, 67%	800 mg 2 times / day multiple, oral Highest studied dose	unhealthy, Mean age 53.7 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inhibitor 2,252 inducer 1,087	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2,057 CYP2B6 926 CYP2C8 1,057 UGT1A1 246 UGT1A9 148 CaV channel 4 P-gp 1,741	UGT1A9 423 CYP2C8 810 UGT1A7 249 UGT1A1 479 UGT1A3 470 UGT1A4 399 UGT1A6 343 UGT1A8 323 UGT1A10 331 UGT2B4 278 UGT2B7 456 UGT2B15 236 UGT2B17 237 P-gp 2,052	CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 2,333	inducer 1,966	no
CYP3A4 2,633	inducer 1,966	no
P-gp 1,932	inhibitor 4,027	yes [IC50 0.84 uM]
UGT1A1 303	inhibitor 4,027	yes [Ki 1.5 uM]
UGT1A9 155	inhibitor 4,027	yes [Ki 1.5 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,946	substrate 4,014	major	no (co-administration study)
UGT1A1 479	substrate 4,014	no
UGT1A10 331	substrate 4,014	no
UGT1A3 470	substrate 4,014	no
UGT1A4 399	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50924	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50924
ChemicalBook	CB42545752	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB42545752
eMolecules	902486	https://www.emolecules.com/cgi-bin/more?vid=902486
MolPort	MolPort-003-850-270	https://www.molport.com/shop/molecule-link/MolPort-003-850-270
ZINC	ZINC000001493878	http://zinc15.docking.org/substances/ZINC000001493878

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PubMed

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Title	Date	PubMed
A phase I clinical and pharmacokinetic study of the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with doxorubicin in patients with solid tumors.	2003 Dec	14692720
Antitumor effect and potentiation or reduction in cytotoxic drug activity in human colon carcinoma cells by the Raf kinase inhibitor (RKI) BAY 43-9006.	2003 Dec	14692718
BAY-43-9006 Bayer/Onyx.	2003 Jun	12901237
B-RAF is a therapeutic target in melanoma.	2004 Aug 19	15208680
Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer.	2004 Nov	15598035

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended daily dose of NEXAVAR (tosylate salt of sorafenib) is 400 mg (2 x 200 mg tablets) taken twice daily, without food (at least 1 hour before or 2 hours after eating). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. 432 433 434 435 436 437 438 439 Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of NEXAVAR therapy. When dose reduction is necessary, the NEXAVAR dose may be reduced to 400 mg once daily. If additional dose reduction is required, NEXAVAR may be reduced to a single 400 mg dose every other day

Route of Administration: Oral

In Vitro Use Guide

Patient-derived glioblastoma cells with low concentrations of sorafenib caused a dramatic dose dependent inhibition of proliferation (IC(50), 1.5 microM) and induction of apoptosis and autophagy. Sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (Stat3) and expression of cyclins, D and E. In contrast, AKT was not modulated by sorafenib

Show entries

Name

Type

Language

SORAFENIB TOSILATE

Preferred Name

English

SORAFENIB TOSYLATE

Official Name

English

SORAFENIB TOSYLATE [ORANGE BOOK]

Common Name

English

4-(4-(((4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)CARBAMOYL)AMINO)PHENOXY)-N-METHYLPYRIDINE-2-CARBOXAMIDE 4-METHYLBENZENESULPHONATE

Systematic Name

English

4-(4-(((4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)CARBAMOYL)AMINO)PHENOXY)-N-METHYLPYRIDINE-2-CARBOXAMIDE 4-METHYLBENZENESULFONATE

Systematic Name

English

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Classification Tree

Code System

Code

Expired

EU-Orphan Drug

EU/3/06/364

Antineoplastic Agent

NCI_THESAURUS

C1742

LIVER NEOPLASMS

EMA ASSESSMENT REPORTS

NEXAVAR (AUTHORIZED: CARCINOMA, HEPATOCELLULAR)

Enzyme Inhibitor

NCI_THESAURUS

C1404

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

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Code System

Code

Type

Description

EPA CompTox

DTXSID9047839

PRIMARY

RXCUI

597744

PRIMARY

RxNorm

NCI_THESAURUS

C2194

PRIMARY

MERCK INDEX

m10116

PRIMARY

Merck Index

CHEBI

50928

PRIMARY

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ACTIVE MOIETY


					9ZOQ3TZI87

SORAFENIB

SUBSTANCE RECORD


					5T62Q3B36J

SORAFENIB TOSYLATE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator