Nilotinib

Absorption

Orally available

Description

Chronic myeloid leukemia (CML), a hematological stem-cell disorder, is definitively diagnosed by the detection of the Philadelphia chromosome, a truncated version of chromosome 22 resulting from the reciprocal translocation of chromosomes 9 and 22 induced by a single mutagenic event. The consequence is the juxtaposition of two genes creating a fusion gene BCR-ABL. This gene leads to the translation of a fusion protein with increased tyrosine kinase activity that contributes to the pathogenesis of CML. Targeting the BCR-ABL protein has led to the successful intervention of the disease. Now established as first-line therapy for CML, imatinib was the first selective tyrosine kinase inhibitor of BCR-ABL. Since imatinib only binds to an inactive conformation of the ABL kinase portion, the conformational restrictions contribute to its selectivity.

Chemical properties

Off-White Solid

Originator

Novartis (Switzerland)

The Uses of Nilotinib

Nilotinib, an orally active signal transduction inhibitor that selectively inhibits the tyrosine kinase Bcr-Abl, was discovered and developed by Norvartis and was launched for the treatment of chronic myeloid leukemia (CML) in patients with Philadelphia chromosome-positive (Ph+) disease who are resistant or intolerant to imatinib mesilate. Additional clinical trials are currently underway for the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GISTs).

The Uses of Nilotinib

Nilotinib (AMN-107) is a Bcr-Abl inhibitor with IC50 less than 30 nM.

The Uses of Nilotinib

Nilotinib-d6, is the labeled analogue of Nilotinib, which might be useful in treatment of chronic myelogenous leukemia.

Background

Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (CML). A Phase I clinical trial in 2006 showed that this drug was relatively safe and offered significant therapeutic benefits in cases of CML which were found to be resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor used as a first-line treatment for CML.

Indications

For the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

What are the applications of Application

Nilotinib is a rationally designed c-Abl and Bcr-Abl kinase inhibitor

Definition

ChEBI: Nilotinib is a member of (trifluoromethyl)benzenes, a member of pyrimidines, a member of pyridines, a member of imidazoles, a secondary amino compound and a secondary carboxamide. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor and an anticoronaviral agent.

brand name

Tasigna

General Description

Class: non-receptor tyrosine kinase
Treatment: CML
Elimination half-life = 17 h
Protein binding >97.5%

Pharmacokinetics

Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML).

Clinical Use

Tyrosine kinase inhibitor:
Treatment of chronic myelogenous leukaemia (CML)

Synthesis

The first step in the synthesis of nilotinib involves the nucleophilic aromatic substitution of 3-fluoro-5-(trifluoromethyl)benzonitrile with 2-methylimidazole. The nitrile is then hydrolyzed with sodium hydroxide in aqueous dioxane. A Curtius rearrangement employing diphenylphosphoryl azide in tert-butanol affords the tert-butyl carbamate. Deprotection of the Boc group provides the 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline piece for the convergent synthesis. Construction of the other half begins with the condensation of 3-amino-4- methylbenzoic acid methyl ester with cyanamide in refluxing ethanolic HCl to generate the 3-guanidinobenzoate. An enamino ketone, prepared by a Claisen condensation of 3-acetylpyridine with ethyl formate in the presence of sodium metal in hot toluene, is then cyclized with the guanidine to yield the pyridylpyrimidine. Following saponification of the ethyl ester, the resultant 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]benzoic acid is finally coupled with the aniline utilizing diethyl cyanophosphate to provide nilotinib.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: avoid with clarithromycin, rifampicin (concentration reduced) and telithromycin.
Antifungals: avoid with itraconazole, ketoconazole (concentration increased) and voriconazole.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: avoid with boceprevir and ritonavir (concentration possibly increased).
Grapefruit juice: avoid concomitant administration.
Avoid concomitant use with other inhibitors or inducers of CYP3A4. Dose alterations may be required.

Metabolism

Not Available

Metabolism

Nilotinib is metabolised in the liver via oxidation and hydroxylation, in which cytochrome P450 isoenzyme CYP3A4 plays an important role. Most of an oral dose is eliminated unchanged in the faeces within 7 days.

References

1) Weisberg?et al.?(2006),?AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL; Br J. Cancer,?94?1765 2) Verstovsek?et al.?(2006),?Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells; Ann. Neurol.,?75?209