vandetanib   Click here for help

GtoPdb Ligand ID: 5717

Synonyms: Caprelsa® | CH 331 | ZD 6474 | ZD-6474 | ZD6474
Approved drug PDB Ligand
vandetanib is an approved drug (FDA (2011), EMA (2012))
Compound class: Synthetic organic
Comment: Vandetanib is a Type-1 kinase inhibitor. It potently inhibits RET, VEGFR-2 (KDR) and EGFR tyrosine kinase activity [2].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 4
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 59.51
Molecular weight 474.11
XLogP 4.14
No. Lipinski's rules broken 0
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Canonical SMILES COc1cc2c(ncnc2cc1OCC1CCN(CC1)C)Nc1ccc(cc1F)Br
Isomeric SMILES COc1cc2c(ncnc2cc1OCC1CCN(CC1)C)Nc1ccc(cc1F)Br
InChI InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
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Summary of Clinical Use Click here for help
Used in the treatment of thyroid cancer.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
VEGFR- and EGFR-dependent signalling pathways have been shown to be involved in some types of cancer, including non-small-cell lung cancer (NSCLC) and RET activity is important in some types of thyroid cancer. Vandetanib potently inhibits VEGFR-2, EGFR and RET tyrosine kinases. It is also a sub-micromolar inhibitor of VEGFR-3 tyrosine kinase.
Pharmacokinetics Click here for help
Vandatenib is absorbed slowly, taking 4-10h to reach peak plasma concentration. Protein binding (albumin and α-1 acid glycoprotein) is approximately 90%. Volume of distributuion is >7L suggesting extensive distribution from the plasma into tissues.
CYP3A4 metabilizes vandatenib to N-desmethyl-vandetanib and the flavin-containing monooxygenase enzymes (FMO1 and FMO3) convert the parent drug to vandetanib-N-oxide. Unchanged vandentanib and its metabolites can be detected in plasma, urine and feces.
Vandatenib is eliminated primarily in the feces (44%) and the urine (25%).
Population pharmacokinetics
Pharmacokinetics of vandatenib are not significantly affected by age or gender. The pharmacokinetics have not been evaluated in children. Japanese and Chinese patients had, on average, exposures that were higher than in white patients receiving the same dose.
Organ function impairment
Hepatic impairment: A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affect exposure to vandetanib. However, vanatenib treatment is not recommended for use in patients with moderate and severe hepatic impairment because safety and efficacy are not well established. Renal impairment: A single dose pharmacokinetic study in volunteers indicated that exposure to vandetanib is enhanced (up to 1.5, 1.6 and 2-fold) in mild, moderate and severe renal impaired subjects respectively, compared to subjects with normal renal function.
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