Imatinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P271：Nur im Freien oder in gut belüfteten Räumen verwenden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Imatinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Chemische Eigenschaften

  Orange Solid

• Verwenden

  Imatinib impurity.

• Verwenden

  antineoplastic

• Verwenden

  Imatinib Mesylate is orally bioavailability mesylate salt of Imatinib, which 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. Imatinib also known as Gleevec, Glivec, CGP-57148B, STI-571 & Imatinib

• Verwenden

  atypical antipsychotic

• Definition

  ChEBI: Imatinib is a benzamide obtained by formal condensation of the carboxy group of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid with the primary aromatic amino group of 4-methyl-N(3)-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine. Used (as its mesylate salt) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours. It has a role as an apoptosis inducer, a tyrosine kinase inhibitor and an antineoplastic agent. It is a N-methylpiperazine, a member of pyridines, a member of benzamides, an aromatic amine and a member of pyrimidines. It is functionally related to a benzamide.

• Indications

  Imantinib mesylate (Gleevec) is a rationally designed inhibitor of the tumor-specific bcr-abl kinase. The Philadelphia chromosome, present in nearly all patients with chronic myelogenous leukemia (CML), is produced by a chromosomal rearrangement linking the bcr and the abl genes. The bcr-able kinase is therefore a unique drug target in leukemic cells, and imantinib selectively and potently inhibits this kinase. Remissions in CML patients are achieved with high frequency and very low toxicity, and this compound may become a front-line agent for treating this cancer. Unfortunately, drug resistance has already been observed in the clinic as a result of mutations in the bcr-abl kinase, and this magic bullet does not appear to be curative for CML patients. Extension of the use of imantinib to other tumor types with overexpression of c-kit kinase or platelet-derived growth factor kinase is undergoing development because of its observed activity against these kinases.

• Indications

  Bcr-Abl inhibitor imatinib (Gleevec(R), Novartis) was approved in 2001 by the FDA. Although fasudil was approved in 1995, imatinib is widely perceived as the first approved SMKI mainly owing to the fact that fasudil's kinase inhibitory mechanism was unknown at the time of approval, and efforts to gain approval of fasudil have been unsuccessful in the United States and Europe.
  The field of kinase inhibitor development has evolved rapidly since the approval of imatinib. Some of the key discoveries and events include (i) the discovery of MAPK/ERK inhibitors, for example, CI-1040 (PD184352), as the first series of type III inhibitors in 2003; (ii) the approval of first dual tyrosine kinase and serine/threonine kinase inhibitor sorafenib in 2005; (iii) the description of the first series of allosteric type IVkinase inhibitor, that is,GNF-2 and analogues that inhibit Bcr–Abl through an allosteric non-ATP-competitivemode, by Gray and coworkers in 2006; (iv) the approval of the first type III inhibitor trametinib in 2013; (v) the approval of the first covalent kinase inhibitors, afatinib and ibrutinib, in 2013; and (vi) the approval of the first lipid kinase inhibitor, that is, the PI3K inhibitor idelalisib, in 2014.
  By December 2016, kinase inhibitor drug discovery can leverage the structures of over 200 human kinases and 5000 kinases of all types, over 1 million publications, clinical data from more than 200 molecules currently in phase I–III trials, and post-marketing results from the approved 38 drugs.

• Allgemeine Beschreibung

  non-receptor tyrosine kinase|
  Treatment: CML, ALL, GIST
  Oral bioavailability = 98%
  Elimination half-life = 20 h
  Protein binding = 95%

• Biologische Aktivität

  imatinib is an inhibitor of protein-tyrosine kinase with ic50 values of 0.1, 0.1 and 0.025μm, respectively against pdgf receptor, c-kit and abl [1].the type 3 group of receptor tyrosine kinases includes pdgfr, csf-1r, flt-3, c-kit and so on. pdgfrs are found in normal tissues, cells as well as some tumors. it is associated with several nonmalignant proliferative diseases. in vitro assays show that imatinib can inhibit both pdgf-aa and pdgf-bb stimulated pdgf receptor phosphorylation. imatinib is also found to inhibit the phosphorylation of c-kit, another kinase which mediates the growth of a number of tumors. imatinib inhibits the phosphorylation of these kinases without effecting the expression of them. some other kinases of the type 3 group (such as fms and flt-3) can’t be inhibited by imatinib, suggesting a selectivity of imatinib. in addition, imatinib is shown to significantly inhibit the bcr-abl tyrosine kinase both in cell-based assay and in vitro kinase assay. moreover, as a downstream pathway of pdgf-mediated signals, map kinase activation can also be effected in rat a10 smooth muscle cells [1].

• Clinical Use

  Tyrosine kinase inhibitor, antineoplastic agent:
  
  Treatment of chronic myeloid leukaemia
  
  Treatment of metastatic malignant gastrointestinal stromal tumours
  
  Treatment of acute lymphoblastic leukaemia

• target

  PDGF receptor

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: concentration reduced by rifampicin - avoid.
  Anticoagulants: enhanced anticoagulant effect of warfarin, replace with heparin.
  Antidepressants: concentration reduced by St. Johns Wort - avoid.
  Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, oxcarbazepine and phenytoin - avoid; absorption of phenytoin possibly reduced.
  Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).
  Antivirals: avoid with boceprevir.
  Ciclosporin: may increase ciclosporin levels.
  Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; concentration of everolimus and possibly ibrutinib increased - reduce dose of everolimus and ibrutinib.
  Tacrolimus: may increase tacrolimus levels.

• Stoffwechsel

  The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites. In vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Based on the recovery of compound(s) after an oral [14C]-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.

• Mode of action

  Imatinib binds close to the ATP-binding site of BCR-ABL and locks it in a closed inactive conformation which excludes ATP. This shuts down its sustained signaling, thus blocking leukemic cell growth.
  

• Einzelnachweise

  [1] elisabeth buchdunger, catherine l. cioffi, norman law, david stover, sayuri ohno-jones, brian j. druker and nicholas b. lydon. abl protein-tyrosine kinase inhibitor sti571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. the journal of pharmacology and experimental therapeutics. 2000, 295(1): 139-145.

Imatinib Upstream-Materialien And Downstream Produkte

Imatinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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