Nilotinib Chemical Properties

Melting point:

231-233 °C

Density 

1.36

storage temp. 

-20°C Freezer

solubility 

Soluble in DMSO (up to 50 mg/ml)

form 

Beige powder.

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.

InChI

InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)

InChIKey

HHZIURLSWUIHRB-UHFFFAOYSA-N

SMILES

N1(C=C(C)N=C1)C1C=C(C=C(C=1)NC(=O)C1C=CC(C)=C(NC2=NC=CC(C3=CC=CN=C3)=N2)C=1)C(F)(F)F

CAS DataBase Reference

641571-10-0(CAS DataBase Reference)

Safety Information

HS Code 

29335990

Hazardous Substances Data

641571-10-0(Hazardous Substances Data)

Nilotinib Usage And Synthesis

Nilotinib for the treatment of chronic myeloid leukemia

Nilotinib is a novel drug for targeted cancer therapy and belongs to tyrosine kinase inhibitors for the treatment of patients of chronic myelogenous leukemia (CML) which is resistant to the Gleevec (imatinib) with an excellent efficacy. Gleevec is the primary-choice drug developed by Novartis Company for the treatment of chronic myelogenous leukemia (CML) .
Nilotinib is the developed through the improvement of the molecular structure of imatinib with a stronger selectivity on the BCR-ABL kinase activity. The inhibitory effect of nilotinib on the tyrosine kinase is 30 times as high as that of imatinib. It is capable of suppressing the activity of the imatinib-resistant BCR-ABL mutant kinase while also being able to inhibit the activity of KIT and PDGFR kinase.
With administration twice daily, nilotinib can targeted to the Bcr-Abl protein, interact with it and inhibit the emergence of cancer cells containing abnormal chromosomes. Bcr-Abl protein is produced by cells containing the abnormal Philadelphia chromosome. For patients of CML, this protein is considered to be an important factor for causing the excessive proliferation of cancer-causing white blood cells.
Approved Uses:
TASIGNA® (nilotinib) capsules is a prescription medicine used to treat:
Adults with newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
Adults with Ph+ CML in chronic phase and accelerated phase who no longer benefit...
https://www.novartis.us

Mechanism of Action

Nilotinib is a selective tyrosine kinase inhibitor active against Bcr-Abl kinase Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. Nilotinib is 30-fold more potent than imatinib.

Absorption, Fate, and Excretion

Nilotinib is rapidly absorbed and reaches its peak concentration in 3 hours. Nilotinib AUC was increased by 82% when given 30 minutes after a high-fat meal compared with a fasting state. Its elimination half-life is approximately 17 hours. It is metabolized by oxidation and hydroxylation as well as undergoing metabolism by CYP3A4. None of the nilotinib metabolites have significant pharmacologic activity.

Drug Interactions

Nilotinib is a competitive inhibitor of cytochrome P-450 (CYP) isoenzymes 3A4, 2C8, 2C9, and 2D6 and has the potential to increase concentrations of drugs metabolized by these enzymes. Nilotinib plasma concentration is increased during concomitant use with potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Decreased nilotinib plasma concentration occurs during concomitant use with potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort). Drugs that increase the pH of the upper gastrointestinal tract may decrease the solubility of nilotinib and reduce its bioavailability. The oral administration of esomeprazole resulted in a 34% reduction in the AUC of nilotinib.

Binding Mode

Both imatinib and nilotinib bind the inactive conformation of ABL, but the latter allows a better topographical fit. As compared to six H-bonds with imatinib， nilotinib makes only four H-bond interactions with the ABL kinase domain, involving the pyridyl N and the backbone amide NHof Met318; the aniline NH and the side chain hydroxyl of Thr315; the amido NH and side chain carboxylate of Glu286; and the amide carbonyl with the backbone NH of the Asp381. The reverse amide group of nilotinib hydrogen bonds to the side chain carboxylate of Glu286 and the backbone NH ofAsp381, similarly to the amide in imatinib as the position of the Glu286 side chain of ABLkinase shifts and twists slightly to interact with the reverse amide. These changes lead to the 4-methylimidazole and the CFs group being highly effective alternative back pocket binders for the N-methylpiperazine group of imatinib. While the basic N-methyl piperazine of imatinib is partially exposed to solvent, forming two H-bonds to the backbone carbonyl group of Ile360 and His361, the methyl-imidazole group and the trifluoromethyl group of nilotinib pack into a unique hydrophobic pocket, making substantial interactions with the ABL kinase domain of the BCR-ABL protein.

Side effects

Nilotinib may cause anemia, neutropenia and thrombocytopenia. Prolonged QT interval and sudden death has occurred. Pruritus, rash, and nausea are common. Also seen with nilotinib are arthralgias and myalgias. Cough has also been associated with nilotinib.

Clinical evaluation

Nilotinib is the other second-generation Abl kinase inhibitor approved for treatment of patients with CML. Nilotinib has increased affinity for the Abl kinase compared with imatinib, binding with an improved topologic fit to the kinase site in its inactive form.Nilotinib is active in chronic and accelerated phase CML patients who have developed resistance to imatinib. As with dasatinib, nilotinib was compared with imatinib in a phase III randomized trial as initial therapy for chronic phase CML patients, with nilotinib achieving higher rates of complete cytogenetic and major molecular responses and with fewer cases of disease progression or clonal evolution in the nilotinib-treated cohorts. Survival outcomes were similar in all arms. Common adverse events with nilotinib included rash, gastrointestinal disturbances (nausea, vomiting, diarrhea), neutropenia, and thrombocytopenia. Pleural effusion and peripheral edema are less common than with dasatinib. In addition, QT prolongation and a risk of pancreatitis are serious side effects of nilotinib.

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

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.

brand name

Tasigna

General Description

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

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

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

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