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)
Uses
Nilotinib (AMN-107) is a Bcr-Abl inhibitor with IC50 less than 30 nM.
Uses
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).
Uses
Nilotinib-d6, is the labeled analogue of Nilotinib, which might be useful in treatment of chronic myelogenous leukemia.
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.
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.
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
