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641571-10-0 分子结构
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4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide

ChemBase编号:4391
分子式:C28H22F3N7O
平均质量:529.5157896
单一同位素质量:529.18379302
SMILES和InChIs

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

引用这个纪录

CBID:4391 http://www.chembase.cn/molecule-4391.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide
IUPAC传统名
nilotinib
商标名
Tasigna (Novartis)
Tasigna
别名
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
CAS号
641571-10-0
MDL号
MFCD09833716
PubChem SID
99443226
160967823
PubChem CID
644241

理论计算性质

理论计算性质

JChem ALOGPS 2.1
Acid pKa 12.861269  质子受体
质子供体 LogD (pH = 5.5) 4.670194 
LogD (pH = 7.4) 5.3314805  Log P 5.36154 
摩尔折射率 152.8501 cm3 极化性 53.47315 Å3
极化表面积 97.62 Å2 可自由旋转的化学键
里宾斯基五规则 false 
Log P 4.51  LOG S -5.42 
溶解度 2.01e-03 g/l 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
Chloroform expand 查看数据来源
DMSO expand 查看数据来源
外观
Off-White to Pale Yellow Solid expand 查看数据来源
熔点
234-236°C expand 查看数据来源
保存条件
-20°C expand 查看数据来源
-20°C Freezer expand 查看数据来源
保存注意事项
IRRITANT expand 查看数据来源
MSDS下载
下载链接 expand 查看数据来源
下载链接 expand 查看数据来源
TSCA收录
false expand 查看数据来源
作用靶点
Bcr-Abl expand 查看数据来源
纯度
95+% expand 查看数据来源
97% expand 查看数据来源
98% expand 查看数据来源
成盐信息
Free Base expand 查看数据来源
质检报告
下载链接 expand 查看数据来源

详细说明

详细说明

DrugBank DrugBank Selleck Chemicals Selleck Chemicals TRC TRC
DrugBank -  DB04868 external link
Item Information
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 external link
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
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.
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
[1] Weisberg E, et al. Blood. 2007, 109(5), 2112-2120.
[2] Liu Y, et al. J Hepatol. 2011, 55(3), 612-625.
[3] Hochhaus A, et al. Cell Cycle. 2011, 10(2), 250-260.
[4] Ammoun S, et al. Neuro Oncol. 2011, 13(7), 759-766.
[5] Rhee CK, et al. Respiration. 2011, 82(3), 273-287.
[6] Weisberg E, et al. Cancer Cell. 2005, 7(2), 129-141.
Toronto Research Chemicals -  N465300 external link
Nilotinib (AMN1O7) might be useful in treatment of chronic myelogenous leukemia.

参考文献

参考文献

供应商提供 Google Scholar IconGoogle Scholar PubMed iconPubMed Google Books IconGoogle Books
  • 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)
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专利

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