4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide

• ChemBase ID: 4391
• Molecular Formular: C28H22F3N7O
• Molecular Mass: 529.5157896
• Monoisotopic Mass: 529.18379302
• SMILES: FC(F)(F)c1cc(n2cc(nc2)C)cc(NC(=O)c2cc(Nc3nc(c4cccnc4)ccn3)c(cc2)C)c1
• Canonical 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)
• InChIKey: HHZIURLSWUIHRB-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide
• IUPAC Traditional name: nilotinib
• Brand Name: Tasigna (Novartis); Tasigna
• Synonyms: 4-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-phenyl)-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide; Tasigna; 4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide; AMN-107; AMN107; nilotinib; Nilotinib; 4-methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-n-(5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide

Database IDs

• CAS Number: 641571-10-0
• MDL Number: MFCD09833716
• PubChem SID: 99443226; 160967823
• PubChem CID: 644241

CALCULATED PROPERTIES

JChem

• Acid pKa: 12.861269
• H Acceptors: 6
• H Donor: 2
• LogD (pH = 5.5): 4.670194
• LogD (pH = 7.4): 5.3314805
• Log P: 5.36154
• Molar Refractivity: 152.8501 cm^3
• Polarizability: 53.47315 Å^3
• Polar Surface Area: 97.62 Å^2
• Rotatable Bonds: 7
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 4.51
• LOG S: -5.42
• Solubility (Water): 2.01e-03 g/l

PROPERTIES

Physical Property

• Solubility: Chloroform; DMSO
• Apperance: Off-White to Pale Yellow Solid
• Melting Point: 234-236°C

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• Storage Warning: IRRITANT
• TSCA Listed: false

Pharmacology Properties

• Target: Bcr-Abl

Product Information

• Purity: 95+%; 97%; 98%
• Salt Data: Free Base

DETAILS

DrugBank - DB04868

• Drug Groups: approved; investigational
• Description: Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (Gleevec®), another tyrosine kinase inhibitor currently used as a first-line treatment. [Wikipedia]
• Indication: For the potential treatment of various leukemias, including chronic myeloid leukemia (CML).
• Pharmacology: 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).
• Affected Organisms: Humans and other mammals
• Absorption: Orally available
• Half Life: 15 hours
• References: Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. [Pubmed] ; Maekawa T, Ashihara E, Kimura S: The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol. 2007 Oct;12(5):327-40. Epub 2007 Oct 22. [Pubmed] ; Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G: Nilotinib Can Override Dasatinib Resistance in Chronic Myeloid Leukemia Patients with Secondary Resistance to Imatinib First-Line Therapy. Acta Haematol. 2007 Sep 20;118(3):162-164. [Pubmed] ; Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P: Nilotinib (formerly AMN107), a highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Aug 22;. [Pubmed] ; Jabbour E, Cortes J, Giles F, O'Brien S, Kantarijan H: Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond. IDrugs. 2007 Jul;10(7):468-79. [Pubmed]
• External Links: Wikipedia

Selleck Chemicals - S1033

Research Area

• Description: Graft-versus-host disease,Malignant melanoma

Biological Activity

• Description: Nilotinib (AMN-107, Tasigna) is a Bcr-Abl inhibitor with IC50 less than 30 nM.
• Targets: Bcr-Abl
• IC50: 30 nM ^[1]
• In Vitro: Nilotinib inhibits proliferation, migration, and actin filament formation, as well as the expression of α-SMA and collagen in activated HSCs. Nilotinib induces apoptosis of HSCs, which is correlated with reduced bcl-2 expression, increases p53 expression, cleavage of PARP, as well as increases expression of PPARγ and TRAIL-R. Nilotinib also induces cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibits activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibits PDGF and TGFβ-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFβ-activated phosphorylated form(s) of Abl in human HSCs are inhibited by Nilotinib. ^[2] Nilotinib inhibits most imatinib-resistant Bcr-Abl mutations, except for T315I. ^[3] Nilotinib inhibits PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFRβ and Akt, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. ^[4] Nilotinib also significantly reduces the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Nilotinib treatment also significantly inhibits the PDGF-induced proliferation of lung fibroblasts. ^[5] Nilotinib inhibits the proliferation of Ba/F3 cells expressing p210- and p190-Bcr-Abl, or K562 and Ku-812F cells with IC50 values ≤12 nM. ^[6]
• In Vivo: Nilotinib reduces collagen deposition and α-SMA expression in CCl₄ and BDL-induced fibrosis. Nilotinib could induce HSC undergoing apoptosis, which is correlated with downregulation of bcl-2. ^[2] Nilotinib attenuates the extent of lung injury and fibrosis. Nilotinib therapy significantly reduces the levels of hydroxyproline on days 14 and 21, which is accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFRβ. ^[5] AMN107 prolongs survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolongs survival in imatinib-resistant CML mouse models. ^[6]
• Clinical Trials: Nilotinib has entered in a phase IV clinical trial in the treatment of philadelphia chromosome positive and chronic myelogenous leukemia in chronic phase.
• Features: Nilotinib is a selective inhibitor of native and mutant Bcr-Abl.

Combination Therapy

• Description: Nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displays stronger efficiency toward tumor growth inhibition, compared with Nilotinib alone. ^[4] Nilotinib plus imatinib has entered in a phase III clinical trial in the treatment of chronic myelogenous leukemia.

Protocol

• Protocol: Cell Assay ^[4]
• Cell Lines: Human primary Schwann and schwannoma cells
• Concentrations: 1-10 μM
• Incubation Time: 72 hours
• Methods: Human primary Schwann and schwannoma cells are seeded on precoated 96-well plates. Nilotinib is added 40 minutes before stimulation with 100 ng/mL PDGF-DD, and cells are cultured for 72 hours (3 days). Because the half-life of Nilotinib is 18 hours, one-half of the originally added concentrations are added freshly every day. In addition to DAPI staining and determination of the total cell number, the more sensitive and accurate BrdU incorporation method is used to detect proliferating cells. Total cell amount (DAPI) and number of dividing cells (BrdU-positive) are blindly counted using an inverted fluorescent microscope and 200 × magnification. All cells in every well are counted. The total cell number per well differed between various cell batches and is 100–300 cells/well.
• Protocol: Animal Study ^[6]
• Animal Models: Systemic 32D Bcr-Abl leukemia model in Female BALB/c mice, Bioluminescent Bcr-Abl model of CML in Female NOD-SCID mice and Bone marrow transplant Bcr-Abl model of CML in syngeneic Balb/c recipient mice
• Formulation: 10% NMP-90% PEG300, PEG300
• Doses: 75 mg/kg, 100 mg/kg
• Administration: Oral administration

References

• References: [1] Weisberg E, et al. Blood. 2007, 109(5), 2112-2120.
• References: [2] Liu Y, et al. J Hepatol. 2011, 55(3), 612-625.
• References: [3] Hochhaus A, et al. Cell Cycle. 2011, 10(2), 250-260.
• References: [4] Ammoun S, et al. Neuro Oncol. 2011, 13(7), 759-766.
• References: [5] Rhee CK, et al. Respiration. 2011, 82(3), 273-287.
• References: [6] Weisberg E, et al. Cancer Cell. 2005, 7(2), 129-141.

Toronto Research Chemicals - N465300

Nilotinib (AMN1O7) might be useful in treatment of chronic myelogenous leukemia.

REFERENCES

• Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. Pubmed
• Maekawa T, Ashihara E, Kimura S: The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol. 2007 Oct;12(5):327-40. Epub 2007 Oct 22. Pubmed
• Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G: Nilotinib Can Override Dasatinib Resistance in Chronic Myeloid Leukemia Patients with Secondary Resistance to Imatinib First-Line Therapy. Acta Haematol. 2007 Sep 20;118(3):162-164. Pubmed
• Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P: Nilotinib (formerly AMN107), a highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Aug 22;. Pubmed
• Jabbour E, Cortes J, Giles F, O'Brien S, Kantarijan H: Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond. IDrugs. 2007 Jul;10(7):468-79. Pubmed
• Ammoun S, et al. Neuro Oncol. 2011, 13(7), 759-766.
• Weisberg E, et al. Cancer Cell. 2005, 7(2), 129-141.
• Weisberg E, et al. Blood. 2007, 109(5), 2112-2120.
• Liu Y, et al. J Hepatol. 2011, 55(3), 612-625.
• Hochhaus A, et al. Cell Cycle. 2011, 10(2), 250-260.
• Rhee CK, et al. Respiration. 2011, 82(3), 273-287.
• Corbin, A., et al.: J. Biol. Chem., 277, 32214(2002)
• Golemovic, M., et al.: Clin. Cancer Res., 11, 4941 (2002)
• Gleixner, K., et al.: Blood, 107, 752 (2002)
• Nicolini, F., et al.: Leukemia, 20, 1061 (2002)