Chemical Properties
Yellow Solid
Uses
Vandetanib (Zactima, ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM.
Uses
Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM
Uses
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of Vandetanib plus Docetaxel was assessed
in patients with previously treated non-small-cell lung cancer (NSCLC).
Uses
Vandetanib is a broad spectrum, orally available kinase inhibitor that targets primarily tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), with IC50 values in the nanomolar range. It also potently blocks non-receptor tyrosine kinases, including ABL, RET, and SRC, as well as several serine/threonine kinases. Primarily because of its effects on receptor tyrosine kinases like VEGFR and EGFR, vandetanib inhibits angiogenesis, cell growth, and metastasis and is effective against certain forms of cancer.[Cayman Chemical]
Description
In April 2011, the U.S. FDA approved vandetanib (ZD6474) for the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in adult patients with inoperable advanced ormetastatic disease. Vandetanib inhibits KDR/VEGFR2, VEGFR3, EGFR, and RET kinases with IC50's of 40, 110, 500, and <100 nM, respectively. In athymic mice bearing MTC tumors, a 14.5-fold reduction of tumor volume was observed after 45 days of treatment with vandetanib at 50 mg/kg/day. The decrease in tumor volume was accompanied by decreases in mitotic index (Ki67) and tumor angiogenesis in treated xenografts. Key steps in the synthesis of vandetanib include the displacement of the chlorine atom from 7-benzyloxy-4-chloro-6-methoxyquinazoline with 4-bromo-2- fluoroaniline under acidic conditions in a protic solvent and a Mitsunobu reaction of a N-protected piperidine alcohol with a phenol.
Originator
Astra Zeneca (United Kingdom)
Definition
ChEBI:Vandetanib is a quinazoline that is 7-[(1-methylpiperidin-4-yl)methoxy]quinazoline bearing additional methoxy and 4-bromo-2-fluorophenylamino substituents at positions 6 and 4 respectively. Used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is an aromatic ether, a secondary amine, a member of quinazolines, a member of piperidines, an organobromine compound and an organofluorine compound.
Brand name
Zactima (AstraZeneca);Caprelsa.
Clinical Use
Vandetanib, an oral VEGF, EGF, and RET receptor tyrosine kinase
inhibitor, was developed by AstraZeneca for the treatment of
symptomatic or aggressive medullary thyroid cancer (MTC) in patients
with advanced or metastatic disease. This is the first drug
approved for the treatment of MTC. Trials for other cancer indications
such as small-cell lung cancer (SCLC), breast cancer, head and
neck cancer, colorectal cancer, hormone-resistant prostate cancer,
and papillary thyroid cancer are currently being explored. While
AstraZeneca had previously developed ZD-4190 which displays
similar efficacy and pharmacokinetic profile to vandetanib, vandetanib
exhibited significantly improved solubility.
Synthesis
Vandetanib contains
a 4-anilinoquinazoline scaffold similar to other EGFR
inhibitors, and the synthesis described below is based on a recent
patent (Scheme).
Commercially available vanillic acid (262) was treated with
benzyl bromide, DIPEA and Et3N to give ethereal ester 263 in 93%
yield. Arene 263 was then subjected to nitration conditions to provide
nitroarene 264 in 86% yield, which underwent immediate
reduction with sodium dithionite in acetonitrile and water to give
aniline 265 in 92% yield. Aniline 265 was then treated with foramidine
acetate in isobutanol which affected an intramolecular cyclization
reaction, giving rise to dihydroquinazolin-4-one 266 in 98%
yield. Heterocycle 266 was treated with phosphorous oxychloride
and the resulting quinazoline chloride was subsequently reacted
with 4-bromo-2-fluoroaniline 267 and trifluoroacetic acid to give
hydroxyaniline 268 in 90% for the three-step sequence. Phenolic
azacycle 268 was then alkylated with sulfonate 269 to furnish
piperidine 270 in 77% yield. Subsequent treatment with formic
acid and aqueous formaldehyde under elevated temperatures gave
vandetanib (XXIII) in 91% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: possibly increased risk of ventricular
arrhythmias with methadone - avoid.
Anti-arrhythmics: possibly increased risk of
ventricular arrhythmias with amiodarone or
disopyramide - avoid.
Antibacterials: possibly increased risk of ventricular
arrhythmias with parenteral erythromycin and
moxifloxacin - avoid; concentration reduced by
rifampicin - avoid.
Antihistamines: possibly increased risk of ventricular
arrhythmias with mizolastine - avoid.
Antimalarials: possibly increased risk of ventricular
arrhythmias with artemether with lumefantrine -
avoid.
Antipsychotics: possibly increased risk of ventricular
arrhythmias with amisulpiride, chlorpromazine,
haloperidol, pimozide, sulpiride and zuclopenthixol
- avoid; avoid concomitant use with clozapine, risk
of agranulocytosis.
Beta-blockers: possibly increased risk of ventricular
arrhythmias with sotalol - avoid.
Cytotoxics: possibly increased risk of ventricular
arrhythmias with arsenic trioxide - avoid.
Hormone antagonist: possibly increased risk of
ventricular arrhythmias with toremifene - avoid.
5HT3
-receptor antagonists: possibly increased risk of
ventricular arrhythmias with ondansetron - avoid.
Pentamidine: possibly increased risk of ventricular
arrhythmias - avoid.
Metabolism
N-desmethyl-vandetanib is primarily produced by
CYP3A4, and vandetanib-N-oxide is primarily produced
by flavin-containing monooxygenase enzymes FMO1
and FMO3.
Unchanged vandentanib and metabolites vandetanib
N-oxide and N-desmethyl vandetanib were detected in
plasma, urine (25
%) and faeces (44
%).
References
Wedge et al. (2002), ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis and tumor growth following oral administration; Cancer Res., 62 4645
Ciardiello et al. (2003), Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase; Clin. Cancer Res., 9 1546
Herbst et al. (2007), Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis; Expert Opin. Investig. Drugs, 16 239
