N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide

• ChemBase编号: 501
• 分子式: C29H31N7O
• 平均质量: 493.60274
• 单一同位素质量: 493.25900865
• SMILES: O=C(Nc1cc(Nc2nc(c3cccnc3)ccn2)c(cc1)C)c1ccc(CN2CCN(CC2)C)cc1
• Canonical SMILES: CN1CCN(CC1)Cc1ccc(cc1)C(=O)Nc1ccc(c(c1)Nc1nccc(n1)c1cccnc1)C
• InChI: InChI=1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)
• InChIKey: KTUFNOKKBVMGRW-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide
• IUPAC传统名: imatinib mesylate; imatinib
• 商标名: Gleevec; Glivec
• 别名: Imatinib Mesylate; Imatinib Methansulfonate; Imatinib; Sti-571; STI571; Gleevec; Glivec; Imatinib(STI571)

登记号

• CAS号: 152459-95-5
• MDL号: MFCD05662257
• PubChem SID: 46505055; 160963964
• PubChem CID: 5291

理论计算性质

JChem

• Acid pKa: 12.454878
• 质子受体: 7
• 质子供体: 2
• LogD (pH = 5.5): 1.6563946
• LogD (pH = 7.4): 3.4515045
• Log P: 4.377673
• 摩尔折射率: 148.9293 cm^3
• 极化性: 57.103134 Å^3
• 极化表面积: 86.28 Å^2
• 可自由旋转的化学键: 7
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 3.47
• LOG S: -4.53
• 溶解度: 1.46e-02 g/l

分子性质

理化性质

• 溶解度: Very soluble in water at pH < 5.5 (mesylate salt)
• 疏水性(logP): 3

安全信息

• 保存条件: -20°C

产品相关信息

• 纯度: 95+%
• 成盐信息: Free Base

详细说明

DrugBank - DB00619

• Drug Groups: approved
• Description: Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is occasionally referred to as CGP57148B or STI571 (especially in older publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.; ; It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.
• Indication: For the treatment Philadelphia chromosome positive chronic myeloid leukemia (CML) and malignant gastrointestinal stromal tumors (GIST).
• Pharmacology: Imatinib is an antineoplastic agent used to treat chronic myelogenous leukemia. Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of Abl with Bcr (breakpoint cluster region), termed Bcr-Abl. As this is now a continuously active tyrosine kinase, Imatinib is used to decrease Bcr-Abl activity.
• Toxicity: Side effects include nausea, vomiting, diarrhea, loss of appetite, dry skin, hair loss, swelling (especially in the legs or around the eyes) and muscle cramps
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic via CYP3A4. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4.
• Absorption: Imatinib is well absorbed with mean absolute bioavailability is 98% with maximum levels achieved within 2-4 hours of dosing
• Half Life: 18 hours for Imatinib, 40 hours for its major active metabolite, the N-desmethyl derivative
• Protein Binding: Very high (95%)
• Elimination: Imatinib elimination is predominately in the feces, mostly as metabolites.
• Clearance: * 8 L/h [50-year-old CML and GIST patient weighing 50 kg]; * 14 L/h [50-year-old CML and GIST patient weighing 100 kg]
• References: Deininger MW, Druker BJ: Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev. 2003 Sep;55(3):401-23. Epub 2003 Jul 17. [Pubmed] ; Vigneri P, Wang JY: Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001 Feb;7(2):228-34. [Pubmed] ; Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL: Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. [Pubmed] ; Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME: Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol. 2004 May;24(5):935-42. Epub 2004 Feb 26. [Pubmed] ; Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D: Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005 Jul;11(7):731-9. Epub 2005 Jun 26. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

DrugBank - DB03261

Drug information: experimental

Selleck Chemicals - S2475

Research Area

• Description: Immunology

Biological Activity

• Description: Imatinib is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM, respectively.
• Targets: v-Abl; PDGFR; c-Kit
• IC50: 600 nM; 100 nM ^[1]; 100 nM ^[2]
• In Vitro: In vitro assays for inhibition of a panel of tyrosine and serine/threonine protein kinases show that Imatinib inhibits the v-Abl tyrosine kinase and PDGFR potently with an IC50 of 0.6 and 0.1 μM, respectively. ^[1] Imatinib inhibits the SLF-dependent activation of wild-type c-kit kinase activity with a IC50 for these effects of approximately 0.1 μM, which is similar to the concentration required for inhibition of PDGFR. ^[2] Imatinib exhibits growth-inhibitory activity on the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 with an IC50 of 32.4 and 32.8 μM, respectively. ^[3] A recent study shows that Imatinib has the potential to exert its antileukemia effects in chronic myelogenous leukemia by down-regulating hERG1 K(+) channels, which are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. ^[4]
• In Vivo: Imatinib produces a different antitumor effect on three xenografted tumors derived from surgical samples of fresh human small cell lung cancers, with 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, and no significant inhibition of SCLC74 growth. ^[5] In high fat fed ApoE(-/-) mice, Imatinib significantly reduces the high fat-induced lipid staining area by 30%, 27% and 35% compared to high-fat diet untreated controls when dosed by gavage at 10, 20 and 40 mg/kg, respectively, and suppresses carotid artery lipid accumulation. ^[6]
• Clinical Trials: Imatinib is currently being investigated in Phase III clinical trials in patients with Sarcoma.

Protocol

• Protocol: Kinase Assay ^[1]
• PDGF receptor kinase activity: PDGF receptor is immunoprecipitated from BALB/c 3T3 cell extracts with rabbit antiserum to the murine PDGF receptor for 2 hours on ice. Protein A-Sepharose beads are used to collect the antigen-antibody complexes. The immunoprecipitates are washed twice with TNET (50 mM Tris, pH 7.5, 140 mM NaCl, 5 mM EDTA, 1% Triton X-100), once with TNE (50 mM Tris, pH 7.5, 140 mM EDTA), and once with kinase buffer (20 mM Tris, pH 7.5,10 mM MgCl₂). After stimulation with PDGF (50 ng/mL) for 10 minutes at 4 °C, different concentrations of drug are added to the reaction mixture. PDGF receptor kinase activity is determined by incubation with 10 μCi [7-^33P]-ATP and l μM ATP for 10 minutes at 4 °C. Immune complexes are separated by SDS-PAGE on 7.5% gels.
• Protocol: Cell Assay ^[3]
• Cell Lines: BON-1 cells and NCI-H727 cells
• Concentrations: ~100 μM
• Incubation Time: 48 hours
• Methods: BON-1 cells and NCI-H727 cells are seeded into flat-bottomed 96-well plates in triplicate and allowed to adhere overnight in 10% fetal bovine serum-supplemented DMEM or RPMI 1640 complete medium, respectively; the medium is then exchanged for serum-free medium (negative control) or serum-free medium containing serial dilutions of Imatinib. After 48 hours (control cultures do not reach confluence), the number of metabolically active cells is determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and absorbance is measured in a Packard Spectra microplate reader at 540 nm. Growth inhibition is calculated using the following formula: inhibition rate = (1 ? a / b) × 100%, where a and b are the absorbance values of the treated and control groups, respectively.
• Protocol: Animal Study ^[5]
• Animal Models: SCLC6, SCLC61, SCLC 74 and SCLC108 small cell lung cancers are injected into Swiss mice (nu/nu, female).
• Formulation: Imatinib is diluted in water.
• Doses: 70 or 100 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Buchdunger E, et al. Proc Natl Acad Sci USA. 1995, 92(7), 2558–2562.
• References: [2] Heinrich MC, et al. Blood. 2000, 96(3), 925-932.
• References: [3] Yao JC, et al. Clin Cancer Res. 2007, 13(1), 234-240.
• References: [4] Zheng F, et al. Med Oncol, 2012, 29(3), 2127-2135.
• References: [5] Decaudin D, et al. Int J Cancer. 2005, 113(5), 849-856.
• References: [6] Ballinger ML, et al. J Cell Mol Med. 2010,14(6B), 1408-1418.

参考文献

• Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL: Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. Pubmed
• Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME: Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol. 2004 May;24(5):935-42. Epub 2004 Feb 26. Pubmed
• Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D: Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005 Jul;11(7):731-9. Epub 2005 Jun 26. Pubmed
• Deininger MW, Druker BJ: Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev. 2003 Sep;55(3):401-23. Epub 2003 Jul 17. Pubmed
• Vigneri P, Wang JY: Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001 Feb;7(2):228-34. Pubmed
• Buchdunger E, et al. Proc Natl Acad Sci USA. 1995, 92(7), 2558–2562.
• Heinrich MC, et al. Blood. 2000, 96(3), 925-932.
• Yao JC, et al. Clin Cancer Res. 2007, 13(1), 234-240.
• Zheng F, et al. Med Oncol, 2012, 29(3), 2127-2135.
• Decaudin D, et al. Int J Cancer. 2005, 113(5), 849-856.
• Ballinger ML, et al. J Cell Mol Med. 2010,14(6B), 1408-1418.