Trametinib
Descripción general
Descripción
Trametinib es un inhibidor de la cinasa de la proteína quinasa activada por mitógeno (MAPK) (MEK) biodisponible por vía oral con actividad antineoplásica. Se une específicamente a MEK1 y MEK2, lo que resulta en la inhibición de la señalización celular mediada por factores de crecimiento y la proliferación celular en varios cánceres . This compound se utiliza principalmente para el tratamiento del melanoma metastásico o irresecable con mutaciones BRAF V600E o V600K .
Aplicaciones Científicas De Investigación
Trametinib tiene una amplia gama de aplicaciones de investigación científica:
Mecanismo De Acción
Trametinib ejerce sus efectos inhibiendo la actividad de MEK1 y MEK2, que son componentes clave de la vía de señalización MAPK / ERK . Esta vía participa en la regulación de la proliferación celular, la supervivencia, la diferenciación y la motilidad . Al inhibir MEK1 y MEK2, this compound previene la fosforilación y activación de las moléculas de señalización descendentes, lo que lleva a la inhibición del crecimiento de las células tumorales .
Análisis Bioquímico
Biochemical Properties
Trametinib specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers . It is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2 . By binding to unphosphorylated MEK1 and MEK2 with high affinity, this compound blocks the catalytic activity of MEKs .
Cellular Effects
This compound has been shown to inhibit the proliferation, migration, and invasion of glioma cells, while inducing apoptosis of glioma cells . It can suppress both the expression of PKM2 in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of ERK1/2 expression . This compound also significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities .
Molecular Mechanism
This compound is a kinase inhibitor that inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo . It functions as an allosteric, ATP noncompetitive inhibitor with nanomolar activity against both MEK 1 and MEK 2 kinases . It maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs .
Temporal Effects in Laboratory Settings
This compound has been shown to have significant effects over time in laboratory settings. For instance, it has been found that this compound can inhibit the growth and intracellular glycolysis of glioma cells by targeting the PKM2/c-Myc pathway . Moreover, this compound treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. For instance, this compound has been shown to significantly enhance remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model . Furthermore, this compound has been shown to inhibit the growth of the transplanted glioma cell tumor .
Metabolic Pathways
This compound is involved in the MAPK pathway, which plays a critical role in cell growth, differentiation, inflammation, and apoptosis . Mutant BRAF proteins signal through MEK1 and MEK2, stimulating cell growth . This compound is metabolized predominantly via deacetylation followed by oxidation and/or glucuronidation .
Transport and Distribution
This compound has limited brain distribution due to active efflux at the blood-brain barrier (BBB) . Following administration, this compound and its metabolites are excreted in the feces (≥81%) and to a minor extent in urine (≤19%) .
Subcellular Localization
This compound is mainly localized in the cytoplasm . It has been shown that this compound can suppress both the expression of PKM2 in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of ERK1/2 expression .
Métodos De Preparación
Rutas de síntesis y condiciones de reacción
La síntesis de trametinib implica varios pasos clave. El material de partida es típicamente una anilina sustituida, que se somete a una serie de reacciones que incluyen ciclización, acilación y halogenación para formar el producto final . Las condiciones de reacción a menudo implican el uso de disolventes orgánicos como el dimetilsulfóxido y reactivos como el cloruro de tionilo .
Métodos de producción industrial
En entornos industriales, la producción de this compound se escala utilizando rutas sintéticas similares, pero con condiciones de reacción optimizadas para garantizar un alto rendimiento y pureza. El proceso implica medidas estrictas de control de calidad para monitorear la formación de impurezas y garantizar que el producto final cumpla con los estándares regulatorios .
Análisis De Reacciones Químicas
Tipos de reacciones
Trametinib se somete a varias reacciones químicas, que incluyen:
Reducción: Las reacciones de reducción también pueden ocurrir, aunque son menos comunes.
Reactivos y condiciones comunes
Oxidación: Los agentes oxidantes comunes incluyen el peróxido de hidrógeno y el permanganato de potasio.
Reducción: Se pueden utilizar agentes reductores como el borohidruro de sodio.
Sustitución: Los reactivos de halogenación como el cloruro de tionilo se utilizan comúnmente.
Principales productos formados
Los principales productos formados a partir de estas reacciones incluyen varios intermediarios e impurezas, como el desacetil this compound y la impureza del ciclopropanamida .
Comparación Con Compuestos Similares
Compuestos similares
Cobimetinib: Otro inhibidor de MEK utilizado en combinación con vemurafenib para el tratamiento del melanoma.
Selumetinib: Un inhibidor de MEK utilizado para el tratamiento de la neurofibromatosis tipo 1.
Singularidad de Trametinib
This compound es único en su capacidad para inhibir selectivamente tanto MEK1 como MEK2 con alta potencia . Ha demostrado una eficacia significativa en combinación con inhibidores de BRAF, como dabrafenib, para el tratamiento de cánceres con mutación BRAF . Se ha demostrado que esta terapia de combinación proporciona una mayor y más prolongada inhibición del crecimiento tumoral en comparación con cualquiera de los fármacos solos .
Propiedades
IUPAC Name |
N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
LIRYPHYGHXZJBZ-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=C2C(=C(N(C1=O)C)NC3=C(C=C(C=C3)I)F)C(=O)N(C(=O)N2C4=CC=CC(=C4)NC(=O)C)C5CC5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C26H23FIN5O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID901007381 |
Source
|
| Record name | N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}ethanimidic acid | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID901007381 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
615.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Trametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 _(MEK1)_ and _MEK2_ activation and of_ MEK1_ and _MEK2_ kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2. |
Source
|
| Record name | Trametinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08911 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
871700-17-3 |
Source
|
| Record name | Trametinib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=871700-17-3 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Trametinib [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0871700173 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Trametinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08911 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}ethanimidic acid | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID901007381 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | N-{3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}acetamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | TRAMETINIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/33E86K87QN | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Melting Point |
293-303 |
Source
|
| Record name | Trametinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08911 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
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