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Imatinib

Time:2016-10-30

Chemical structure

Chemical data

Clinical data

250px-Imatinib2DACS.svg

 

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Formula C29H31N7O Trade names Gleevec, Glivec
Molar mass 493.603 g/mol Bioavailability 98%
589.7 g/mol (mesilate) Protein binding 95%
CAS Number 152459-95-5 Metabolism Hepatic (mainly CYP3A4-mediated)
220127-57-1 (mesilate) Biological half-life 18 h (imatinib)
40 h (active metabolite)
Research code STI-571; CGP-57148B
Systematic (IUPAC) name 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide

Description

Imatinib (INN), marketed by Novartis as Gleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Imatinib kills cancer cells by turning off tyrosine kinases. In order to survive, cells need signaling through proteins (signal cascade) to keep them alive. Some of the proteins in this cascade use a phosphate group as an “on” switch. This phosphate group is added by a tyrosine kinase enzyme. In healthy cells, these tyrosine kinase enzymes are turned on and off as needed. In Ph-positive CML cells, one tyrosine kinase enzyme, BCR-Abl, is stuck on the “on” position, and keeps adding phosphate groups. Imatinib blocks this BCR-Abl enzyme, and stops it from adding phosphate groups. As a result, these cells stop growing, and even die by a process of cell death (apoptosis). Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form oftargeted therapy—only cancer cells are killed through the drug’s action. In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.

Due in large part to the development of Gleevec and related drugs having a similar mechanism of action, the five year survival rate for people with chronic myeloid leukemia nearly doubled from 31% in 1993 (before Gleevec’s 2001 FDA approval) to 59% for those diagnosed between 2003 and 2009. Compared to older drugs imatinib has a relatively benign side effect profile, allowing many patients to live a normal lifestyle. Median survival for imatinib-treated people with gastrointestinal stromal tumors (GIST) is nearly 5 years compared to 9 to 20 months in the pre-imatinib-era.

Physicians have written that the cost of imatinib, averaging $120,000 a year in 2016, is excessive. In the USA, the patent protecting the active principle expired on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019. In India, the patent was rejected in an Indian Supreme Court decision in 2013.

It is on the World Health Organization’s List of Essential Medicines, a list of the medications needed to cover the majority of health care needs in a health system. The developers of imatinib were awarded the Lasker Award in 2009 and the Japan Prize in 2012. Gleevec is the beta crystalline form of imatinib mesilate, the mesylate salt of imatinib.

 

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