nilotinib   Click here for help

GtoPdb Ligand ID: 5697

Synonyms: AMN 107 | AMN107 | Tasigna®
Approved drug PDB Ligand
nilotinib is an approved drug (FDA & EMA (2007))
Compound class: Synthetic organic
Comment: Nilotinib is a Type-2 kinase inhibitor and was first approved by the FDA in 2007.
Preclinical studies in rodent Parkinson's disease models suggest that nilotinib has some potential to promote autophagic degradation of α-synuclein [4-6,9], a brain protein whose accumulation and aggregation contributes to the formation of toxic insoluble fibrils which cause pathological changes such as neuronal loss in Parkinson's disease and other synucleinopathies. This mechanism has been evaluated in a pilot, proof-of-concept and safety clinical trial in a small number of patients with Parkinson's disease- and diffuse Lewy body disease-associated cognitive impairment (see NCT02281474; note that this trial is not placebo controlled or blinded).
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 8
Topological polar surface area 97.1
Molecular weight 529.18
XLogP 4.93
No. Lipinski's rules broken 0
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Canonical SMILES Cc1ncn(c1)c1cc(NC(=O)c2ccc(c(c2)Nc2nccc(n2)c2cccnc2)C)cc(c1)C(F)(F)F
Isomeric SMILES Cc1ncn(c1)c1cc(NC(=O)c2ccc(c(c2)Nc2nccc(n2)c2cccnc2)C)cc(c1)C(F)(F)F
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)
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Summary of Clinical Use Click here for help
Used in the treatment of chronic myelogenous leukemia.
Marketed formulations contain nilotinib hydrochloride monohydrate (PubChem CID 16757572).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukemia cells. The substance binds with high affinity to the ATP-binding site of wild-type and 32/33 imatinib-resistant mutant forms of BCR-ABL. Nilotinib also targets c-Kit and PDGFR but has little or no effect against the majority of other protein kinases examined, including Src.
Pharmacokinetics Click here for help
Peak concentrations of nilotinib are reached 3 hours after oral administration. Plasma protein binding is approximately 98%. Bioavailability of nilotinib is increased if administered after food.
Nilotinib is primarily metabolised by CYP3A4, with possible minor contribution from CYP2C8. None of the metabolites contribute significantly to the pharmacological activity of nilotinib.
More than 90% of the dose is eliminated within 7 days, mainly in feces.
Population pharmacokinetics
Pharmacokinetics of nilotinib are not significantly affected by age, body weight, race, or gender.
Organ function impairment
The effect of renal function impairment on the pharmacokinetics of nilotinib has not been investigated. Total exposure to nilotinib is increased with hepatic function impairment.
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