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Imatinib
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| Systematic (IUPAC) name | |
| 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3- [(4-pyridin-3-ylpyrimidin-2-yl)amino]-phenyl]- benzamide |
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| Identifiers | |
| CAS number | 220127-57-1 (mesilate) |
| ATC code | L01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C29H31N7O |
| Mol. mass | 493. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 603 g/mol 589. 7 g/mol (mesilate) |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 98% |
| Protein binding | 95% |
| Metabolism | Hepatic (mainly CYP3A4-mediated) |
| Half life | 18 hours (imatinib) 40 hours (active metabolite) |
| Excretion | Fecal (68%) and renal (13%) |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
Imatinib is a drug used to treat certain types of cancer. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of A drug's efficiency may be affected by the degree to which it binds to the proteins within Blood plasma. Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals Cytochrome P450 3A4 (abbreviated CYP3A4) ( a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The kidneys are complicated organs that have numerous biological roles The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). Novartis International AG is a multinational Pharmaceutical company based in Basel Switzerland that manufactures drugs such as Clozapine The United States of America —commonly referred to as the For a topic outline on this subject see List of basic Australia topics. In Chemistry, a mesylate is any Salt or Ester of Methanesulfonic acid ( C[[Hydrogen H]]3 S[[Oxygen O]]3H An International Nonproprietary Name ( INN; also known as rINN, for recommended International Nonproprietary Name or pINN for proposed It was originally coded during development as CGP57148B or STI-571 (these terms are used in early preclinical publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. Chronic myelogenous (or myeloid leukemia ( CML) is a form of Leukemia characterized by the increased and unregulated growth of predominantly Myeloid cells A gastrointestinal stromal tumor ( GIST) is a rare Tumor of the Gastrointestinal tract (1-3% of all gastrointestinal malignancies Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled
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. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells.
Contents |
Molecular pharmacology
Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. In Organic chemistry, the phenyl group or phenyl ring (often abbreviated as -Ph) is the Functional group with the formula - Amines are Organic compounds and Functional groups that contain a basic Nitrogen Atom with a Lone pair. Pyrimidine is a Heterocyclic Aromatic Organic compound similar to Benzene and Pyridine, containing two Nitrogen Atoms It occupies the TK active site, leading to a decrease in activity.
There are a large number of TK enzymes in the body, including the insulin receptor. In Molecular biology, the insulin receptor is a transmembrane receptor that is activated by Insulin. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor). Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with Chronic myelogenous leukemia (CML CD117, also called KIT or C-kit receptor, is a Cytokine receptor expressed on the surface of Hematopoietic stem cells as well as other cell types The platelet-derived growth factors PDGF-A and -B have for already more than 30 years been recognized as important factors regulating Cell proliferation, Cellular In Molecular biology, Platelet-derived growth factor ( PDGF) is one of the numerous Growth factors or Proteins that regulate cell growth
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. Chronic myelogenous (or myeloid leukemia ( CML) is a form of Leukemia characterized by the increased and unregulated growth of predominantly Myeloid cells Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with Chronic myelogenous leukemia (CML As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein.
The active sites of tyrosine kinases each have a binding site for ATP. The active site of an Enzyme contains the catalytic and Binding sites. In Biochemistry, a binding site is a region on a Protein, DNA, or RNA to which specific other Molecules and Ions &mdash Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Catalysis is the process in which the rate of a Chemical reaction is increased by means of a Chemical substance known as a catalyst A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule Imatinib works by binding to the ATP binding site of bcr-abl and inhibiting the enzyme activity of the protein competitively. Enzyme inhibitors are Molecules that bind to Enzymes and decrease their activity.
Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumour cells, however, have a dependence on bcr-abl. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled [1] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions. [2]
Uses
Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. Chronic myelogenous (or myeloid leukemia ( CML) is a form of Leukemia characterized by the increased and unregulated growth of predominantly Myeloid cells A gastrointestinal stromal tumor ( GIST) is a rare Tumor of the Gastrointestinal tract (1-3% of all gastrointestinal malignancies Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled One study demonstrated that Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit. Mastocytosis is a group of rare disorders of both children and adults caused by the presence of too many Mast cells ( mastocytes) and CD34 + mast [3] Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans. The hypereosinophilic syndrome (HS is a disease process characterized by a persistently elevated eosinophil count (≥ 1500 eosinophils/mm³ in the blood for at least six months without Dermatofibrosarcoma protuberans (DFSP is a rare Neoplasm of the Dermis layer of the skin and is classified as a Sarcoma.
In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). A laboratory (informally lab) is a facility that provides controlled conditions in which scientific Research, Experiments and In Molecular biology, Platelet-derived growth factor ( PDGF) is one of the numerous Growth factors or Proteins that regulate cell growth One of its effects is delaying atherosclerosis in mice with diabetes. Atherosclerosis is a Disease affecting arterial Blood vessels It is a chronic inflammatory response in the walls of arteries in large part due to the accumulation A mouse (plural mice) is a small Animal that belongs to one Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc [4]
Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur. Emory University is a Private university located in the metropolitan area of the city of Atlanta and in western unincorporated DeKalb County, Smallpox is an Infectious disease unique to humans caused by either of two virus variants named Variola major and Variola minor. [5]
Gleevec is also being used in the treatment of certain brain tumors to include high grade glioblastoma.
Tolerability and side effects
In the United States, the Food and Drug Administration has approved imatinib as first-line treatment for CML. The United States of America —commonly referred to as the [1] Imatinib has passed through Phase III trials for CML, and has been shown to be more effective than the previous standard treatment of α-interferon and cytarabine. Interferons ( IFN s are natural Proteins produced by the cells of the Immune system of most Vertebrates in response to challenges by foreign agents Cytarabine, or cytosine arabinoside, is a Chemotherapy agent used mainly in the treatment of hematological malignancies such as Leukemia Although the long-term side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated (eg. In Medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as Chemotherapy or Surgery. liver toxicity was much less than predicted). Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild. Oedema (or Edema in American English formerly known as dropsy or hydropsy, is the increase of Interstitial fluid in any organ &mdash swelling Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort A rash is a change of the Skin which affects its color appearance or Texture.
Severe congestive cardiac failure is an uncommon but recognised side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply [6]
Metabolism
Metabolism of imatinib occurs in the liver and the main metabolite, N-demethylated piperazine derivative, is also active. Piperazine is an Organic compound that consists of a six-membered ring containing two opposing nitrogen atoms The major route of elimination is in the bile, only a small portion is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively. Half-Life (computer-game page here It's already listed in the disambiguation page
History
Imatinib was identified in the late 1990s by Novartis chemists. The 1990s collectively refers to the years between and including 1990 and 1999 Dr Brian J. Druker led many of the key clinical trials confirming the efficacy of imatinib in CML. Chronic myelogenous (or myeloid leukemia ( CML) is a form of Leukemia characterized by the increased and unregulated growth of predominantly Myeloid cells Its development is the template for rational drug design. Drug design is the approach of finding drugs by design based on their Biological targets Typically a drug target is a key Molecule involved in a particular Soon after identification of the bcr-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. High-throughput screening (HTS is a method for scientific Experimentation especially used in Drug discovery and relevant to the fields of Biology and This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib. [7]
Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the "magic bullet" to cure cancer. Time (trademarked in capitals as TIME) is a weekly American Newsmagazine, similar to Newsweek and
Gleevec, which costs $32,000 per year for a 400 mg/day dose, is often cited as an example of pharmaceutical industry innovation that justifies the high cost of drugs. Marcia Angell and Arnold S. Marcia Angell MD (born 1939 is an American physician author and the first woman to serve as editor-in-chief of the New England Journal of Medicine Relman argue that Gleevec is actually an example of the contribution of taxpayer-supported research and of industry inaction. Drucker tested several, and imatinib was the most potent, and unusually, had almost no effect on normal cells. Novartis had "little corporate enthusiasm," they write, but Drucker persisted[8].
In 2007, imatinib became a test case through which Novartis challenged India's patent laws. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. A test case in Software engineering is a set of conditions or variables under which a tester will determine if a Requirement or Use case upon India, officially the Republic of India (भारत गणराज्य inc-Latn Bhārat Gaṇarājya; see also other Indian languages) is a country This would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Organisations such as Médecins Sans Frontières argue that a change in law would make it impossible for Indian companies to produce cheap antiretrovirals (anti-AIDS medication), endangering access to these drugs in Third World countries. Médecins Sans Frontières (pronounced) or Doctors Without Borders, is a secular humanitarian-aid Non-governmental organization best known [9] On 6 August 2007 The High Court in Chennai, India, dismissed the writ petition filed by Novartis, challenging the constitutionality of Section 3(d)of Indian Patent Act and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question.
See also
References
- ^ a b Deininger M, Druker BJ. The era of cancer Chemotherapy began in the 1940s with the first use of Nitrogen mustards and Folic acid antagonist drugs Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev 2003;55:401-423. PMID 12869662.
- ^ Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001:7:228-234. PMID 11175855
- ^ 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. PMID 16779792
- ^ 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;24:935-42. PMID 14988091
- ^ Reeves P, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg M, Veach D, Bornmann W, Sherman M, Kalman D (2005). Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med 11 (7): 731-9. PMID 15980865
- ^ Risto Kerkelä, Luanda Grazette, Rinat Yacobi, et al. . "Cardiotoxicity of the cancer therapeutic agent imatinib mesylate". Nature Med 12: 908–16.
- ^ Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. PMID 10619854
- ^ [1]How the drug industry distorts medicine and politics: America’s Other Drug Problem, By Arnold S. Relman and Marcia Angell, New Republic, December 16, 2002
- ^ Médecins Sans Frontières. Médecins Sans Frontières (pronounced) or Doctors Without Borders, is a secular humanitarian-aid Non-governmental organization best known "As Novartis Challenges India's Patent Law, MSF Warns Access to Medicines Is Under Threat", 2006-09-26. Year 2006 ( MMVI) was a Common year starting on Sunday of the Gregorian calendar. Events 46 BC - Julius Caesar dedicates a Accessed 2006-02-10. Year 2006 ( MMVI) was a Common year starting on Sunday of the Gregorian calendar. Events 1355 - The St Scholastica's Day riot breaks out in Oxford, England, leaving 63 scholars and perhaps 30 locals dead
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