Imatinib Mesylate

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H31N7O.CH4O3S
Molecular Weight	589.708
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CS(O)(=O)=O.CN1CCN(CC2=CC=C(C=C2)C(=O)NC3=CC(NC4=NC(=CC=N4)C5=CC=CN=C5)=C(C)C=C3)CC1

InChI

InChIKey=YLMAHDNUQAMNNX-UHFFFAOYSA-N

InChI=1S/C29H31N7O.CH4O3S/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36;1-5(2,3)4/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34);1H3,(H,2,3,4)

HIDE SMILES / InChI

Description

Imatinib (GLEEVEC®) is a tyrosine kinase inhibitor and antineoplastic agent that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukaemia (CML). It inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive CML. Imatinib (GLEEVEC®) inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. It is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib (GLEEVEC®) inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Bcr/Abl fusion protein 16	Inhibitor 8,297	0.025 µM [IC50]
Platelet-derived growth factor receptor alpha 30	Inhibitor 8,297	0.1 µM [IC50]
Stem cell growth factor receptor 53	Inhibitor 8,297	0.1 µM [IC50]
Platelet-derived growth factor receptor beta 56	Inhibitor 8,297	39.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Philadelphia chromosome positive chronic myeloid leukemia 3	Primary	Approved 8,429	GLEEVEC
Philadelphia chromosome positive acute lymphoblastic leukemia 7	Primary	Approved 8,429	GLEEVEC
Myelodysplastic/myeloproliferative diseases associated with PDGFR 3	Primary	Approved 8,429	GLEEVEC
Aggressive systemic mastocytosis (D816V c-Kit mutation status negative/c-Kit mutational status unknown) 3	Primary	Approved 8,429	GLEEVEC
Hypereosinophilic syndrome 3	Primary	Approved 8,429	GLEEVEC

C_max

Value	Dose	Analyte	Population
1.74 mg/L	400 mg single, oral	IMATINIB plasma	Homo sapiens
4478 ng/mL	500 mg 2 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
1907.5 ng/mL	400 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
3508.9 ng/mL	600 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
1907.5 ng/mL	400 mg single, oral	IMATINIB plasma	Homo sapiens
4.82 μg/mL	600 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
4.75 μg/mL	500 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
0.71 μg/mL	600 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens
1.18 μg/mL	500 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
19.9 mg × h/L	400 mg single, oral	IMATINIB plasma	Homo sapiens
174.1 ng × h/mL	500 mg 2 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
38.8 ng × h/mL	400 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
89.9 ng × h/mL	600 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
38.8 μg × h/mL	400 mg single, oral	IMATINIB plasma	Homo sapiens
63.7 μg × h/mL	600 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
97.3 μg × h/mL	500 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
10.1 μg × h/mL	600 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens
19.7 μg × h/mL	500 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
15.8 h	400 mg single, oral	IMATINIB plasma	Homo sapiens
17 h	500 mg 2 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
14.8 h	400 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
15.6 h	600 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
83.3 h	600 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
23.6 h	500 mg 2 times / day multiple, oral	IMATINIB plasma	Homo sapiens
50.8 h	600 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens
10.2 h	500 mg 2 times / day multiple, oral	CGP-74588 plasma	Homo sapiens

F_unbound

Value	Dose	Analyte	Population
4%	500 mg 2 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
4%	400 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
4%	600 mg 1 times / day steady-state, oral	IMATINIB plasma	Homo sapiens
5%	400 mg single, oral	IMATINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
500 mg 2 times / day steady, oral MTD	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35
400 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35	DLT: Transaminases increased...
600 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35	DLT: Neutropenia, Hypocalcemia...

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AEs

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AE	Significance	Dose	Population
Transaminases increased	grade 3, 1 patient DLT	400 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35
Emesis	grade 3, 2 patients DLT	600 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35
Hypokalemia	grade 3, 2 patients DLT	600 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35
Nausea	grade 3, 2 patients DLT	600 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35
Neutropenia	grade 3, 2 patients DLT	600 mg 2 times / day steady, oral	unhealthy, 53.3 years (range: 29.8–69.9 years) n = 35

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	substrate 1,037 inhibitor 1,767	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 278 CYP1A2 1,524 CYP2A6 707 CYP2C19 1,478 CYP2B6 810 CYP2E1 882 CYP4A9/11 37	CYP3A5 395 CYP1A2 1,054 CYP2C8 693 CYP2C19 991

Drug as perpetrator

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Target	Modality	Activity
CYP2B6 1,001	inhibitor 3,277	no
CYP2E1 970	inhibitor 3,277	no
CYP4A9/11 37	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	yes [IC50 120 uM]
CYP2A6 739	inhibitor 3,277	yes [IC50 230 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	minor
CYP2C19 991	substrate 3,367	minor
CYP2C8 693	substrate 3,367	minor
CYP2C9 1,037	substrate 3,367	minor

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Tox targets

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

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45783	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45783
ChemicalBook	CB7370890	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7370890
MolPort	MolPort-000-883-342	https://www.molport.com/shop/molecule-link/MolPort-000-883-342
Selleck Chemicals	Imatinib(STI571)	http://www.selleckchem.com/products/Imatinib(STI571).html
ZINC	ZINC000019632618	http://zinc15.docking.org/substances/ZINC000019632618

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PubMed

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Title	Date	PubMed
STI571: targeting BCR-ABL as therapy for CML.	2001	11423669
Mechanisms of transformation by the BCR/ABL oncogene.	2001 Apr	11345193
PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis.	2001 Apr	11260393
In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents.	2001 Apr 1	11264164
ARG tyrosine kinase activity is inhibited by STI571.	2001 Apr 15	11290609

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Patents

Sample Use Guides

In Vivo Use Guide

The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Route of Administration: Oral

In Vitro Use Guide

Imatinib (CGP 57148) was tested for growth inhibition of EGF-dependent BALB/MK cells, the H-ras-transformed T24 bladder carcinoma line, and IL-3-dependent growth of FDC-Pl cells. The compound showed only weak antiproliferative activity against these cell lines, with IC50 values of 12.7 uM, 9.4 uM, and 29.2 uM, respectively. However, when tested on v-abl-transformed PB-3c cells, incubation with CGP 57148 resulted in potent growth inhibition even in the presence of exogenous IL-3 (IC50 values, 0.11 uM without IL-3 and 0.9 uM with IL-3). Similar results were obtained using v-sis-transformed BALB/c 3T3 cells, which grow in response to autocrine PDGF production (IC50, 0.33 uM).

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Name

Type

Language

Imatinib Mesylate

Official Name

English

IMATINIB MESYLATE [USAN]

Common Name

English

IMATINIB METHANE SULFONATE

Common Name

English

IMATINIB METHANESULFONATE

Common Name

English

IMATINIB ACCORD

Brand Name

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

209005

LEUKEMIA, LYMPHOID

EMA ASSESSMENT REPORTS

IMATINIB ACCORD (AUTHORIZED: PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA

ESOSINOPHILIA

EMA ASSESSMENT REPORTS

IMATINIB MEDAC (AUTHORIZED: HYPEREOSINOPHILIC SYNDROME)

MYELOPROLIFERATIVE DISORDERS

EMA ASSESSMENT REPORTS

IMATINIB ACTAVIS (AUTHORIZED: LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE)

MYELOPROLIFERATIVE DISORDERS

EMA ASSESSMENT REPORTS

GLIVEC (AUTHORIZED: LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE)

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Code System

Code

Type

Description

HSDB

7142

PRIMARY

RXCUI

284924

PRIMARY

RxNorm

EPA CompTox

DTXSID9040502

PRIMARY

MERCK INDEX

m6213

PRIMARY

Merck Index

EVMPD

SUB12517MIG

PRIMARY

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ACTIVE MOIETY


					BKJ8M8G5HI

IMATINIB

SUBSTANCE RECORD


					8A1O1M485B

Imatinib Mesylate

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