Vandetanib

Absorption

Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months.

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 IC_50'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.

Chemical properties

Yellow Solid

Originator

Astra Zeneca (United Kingdom)

The Uses of Vandetanib

Vandetanib (Zactima, ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM.

The Uses of Vandetanib

Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM

The Uses of Vandetanib

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).

The Uses of Vandetanib

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]

What are the applications of Application

Vandetanib is an antagonist of VEGFR (Flk and Flk) and EGFR families.

Background

Vandetanib is an oral once-daily kinase inhibitor of tumour angiogenesis and tumour cell proliferation with the potential for use in a broad range of tumour types.
On April 6 2011, vandetanib was approved by the FDA to treat nonresectable, locally advanced, or metastatic medullary thyroid cancer in adult patients.

Indications

Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated heart failure.

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.

General Description

Class: receptor tyrosine kinase; Treatment: RET-altered thyroid cancers; Other name: AZD-6474; Elimination half-life = 19 days; Protein binding = 90%

Pharmacokinetics

Mean IC50 of approximately 2.1 μg/mL.

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

Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3.

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
%).

storage

Store at -20°C

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