imatinib

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Ligands
imatinib

GtoPdb Ligand ID: 5687

Synonyms: CGP 57148 | Gleevec® | Glivec® | STI571

imatinib is an approved drug (FDA & EMA (2001))

Compound class: Synthetic organic

Comment: Imatinib is a Type-2 kinase inhibitor. Its main inhibitory activity is against ABL kinase, but it has significant action at secondary targets including platelet-derived growth factor receptor (PDGFR) and stem cell growth factor receptor (KIT).

Coronavirus: imatinib is reported to block Spike protein-induced SARS-CoV and MERS-CoV fusion in vitro [8], potentially by blocking Abl2 at the endosomal membrane and disrupting the actin dynamics that are required for virus-host fusion [2]. It will be informative to determine if this holds true for SARS-CoV-2, and whether re-purposing of imatinib and/or newer Abl kinase inhibitors (dasatinib, bosutinib, ponatinib, nilotinib) could be a viable strategy against COVID-19. This approach would likely to be most effective during the early stage of infection.

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: imatinib

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	8
Hydrogen bond donors	2
Rotatable bonds	8
Topological polar surface area	86.28
Molecular weight	493.26
XLogP	3.04
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	CN1CCN(CC1)Cc1ccc(cc1)C(=O)Nc1ccc(c(c1)Nc1nccc(n1)c1cccnc1)C
Isomeric SMILES	CN1CCN(CC1)Cc1ccc(cc1)C(=O)Nc1ccc(c(c1)Nc1nccc(n1)c1cccnc1)C
InChI	InChI=1S/C29H31N7O/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/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)
InChI Key	KTUFNOKKBVMGRW-UHFFFAOYSA-N

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Summary of Clinical Use
Used in the treatment of multiple cancers including chronic myelogenous leukemia and gastrointestinal stromal tumours (GIST). Adjuvant imatinib is recommended for KIT-mutated GISTs. The clinically administered form is the Imatinib mesilate (mesylate) salt (PubChem CID 123596). Generic imatinib mesylate tablets were approved by the US FDA in December 2015, as therapeutic equivalents of Novartis' original Gleevec.

Summary of Clinical Use

Used in the treatment of multiple cancers including chronic myelogenous leukemia and gastrointestinal stromal tumours (GIST). Adjuvant imatinib is recommended for KIT-mutated GISTs. The clinically administered form is the Imatinib mesilate (mesylate) salt (PubChem CID 123596).
Generic imatinib mesylate tablets were approved by the US FDA in December 2015, as therapeutic equivalents of Novartis' original Gleevec.

Mechanism Of Action and Pharmacodynamic Effects
Imatinib is a protein-tyrosine kinase inhibitor that inhibits proliferation and induces apoptosis in Bcr-Abl leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia (CML) and as such is an antineoplastic agent. Imatinib acts to reduce the abnormal constitutive activity of Bcr-Abl tyrosine kinase in CML. Additional imatinib targets include the tyrosine kinase receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF, c-Kit) where it has been shown to inhibit PDGF- and SCF-mediated cellular events.

Mechanism Of Action and Pharmacodynamic Effects

Imatinib is a protein-tyrosine kinase inhibitor that inhibits proliferation and induces apoptosis in Bcr-Abl leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia (CML) and as such is an antineoplastic agent. Imatinib acts to reduce the abnormal constitutive activity of Bcr-Abl tyrosine kinase in CML. Additional imatinib targets include the tyrosine kinase receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF, c-Kit) where it has been shown to inhibit PDGF- and SCF-mediated cellular events.

Pharmacokinetics
Absorption/Distribution
Imatinib is well absorbed (peaking 2-4h after administration) with bioavailability reaching 98%. 95% of circulating imatinib is protein bound.
Biotransformation/Metabolism
CYP4A4 in the liver is the major metabolic enzyme converting imatinib to its main circulating (and active) derivative, N-demethylated piperazine. CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play minor roles in its metabolism.
Elimination
Imatinib excretion, mainly as metabolites, is predominately in the feces (68%) with a minor amount eliminated in the urine (13%).
Population pharmacokinetics
No clinically significant change in pharmacokinetics due to age, weight or gender has been reported and in children pharmacokinetics are similar to those in adults.
Organ function impairment
Patients with severe renal impairment may show raised exposure to imatinib and its metabolites compared to patients with healthy renal function, as do patients with severe hepatic impairment.

Pharmacokinetics

Absorption/Distribution

Imatinib is well absorbed (peaking 2-4h after administration) with bioavailability reaching 98%. 95% of circulating imatinib is protein bound.

Biotransformation/Metabolism

CYP4A4 in the liver is the major metabolic enzyme converting imatinib to its main circulating (and active) derivative, N-demethylated piperazine. CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play minor roles in its metabolism.

Elimination

Imatinib excretion, mainly as metabolites, is predominately in the feces (68%) with a minor amount eliminated in the urine (13%).

Population pharmacokinetics

No clinically significant change in pharmacokinetics due to age, weight or gender has been reported and in children pharmacokinetics are similar to those in adults.

Organ function impairment

Patients with severe renal impairment may show raised exposure to imatinib and its metabolites compared to patients with healthy renal function, as do patients with severe hepatic impairment.