Perampanel
Descripción general
Descripción
Perampanel es un nuevo fármaco antiepiléptico que funciona como un antagonista selectivo y no competitivo del receptor de ácido α-amino-3-hidroxi-5-metil-4-isoxazolopropiónico. Se utiliza principalmente como terapia adyuvante para el tratamiento de las crisis parciales y las crisis tónico-clónicas generalizadas primarias en pacientes con epilepsia . This compound se comercializa bajo la marca Fycompa y ha sido aprobado en más de 35 países .
Mecanismo De Acción
Perampanel ejerce sus efectos inhibiendo selectivamente el receptor de ácido α-amino-3-hidroxi-5-metil-4-isoxazolopropiónico, que participa en la transmisión sináptica excitatoria en el cerebro . Al bloquear la actividad de este receptor, this compound reduce la excitación neuronal y ayuda a controlar las convulsiones . Los objetivos moleculares exactos y las vías implicadas en este mecanismo aún se están estudiando, pero se sabe que this compound tiene una vida media terminal prolongada y está altamente unido a las proteínas plasmáticas .
Análisis Bioquímico
Biochemical Properties
Perampanel plays a crucial role in inhibiting neuronal excitation in the central nervous system by blocking AMPA receptors. These receptors are ligand-gated ion channels that mediate fast synaptic transmission in the central nervous system. By inhibiting these receptors, this compound reduces the excitatory neurotransmission that can lead to seizures . This compound interacts with various biomolecules, including proteins such as protein kinase C (PKC), Ca2±calmodulin-dependent protein kinase II (CAMKII), protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) .
Cellular Effects
This compound affects various types of cells and cellular processes. It influences cell function by modulating cell signaling pathways, gene expression, and cellular metabolism. In normal and epileptic rats, this compound has been shown to affect the phosphorylation of GluA1, a subunit of the AMPA receptor, through the regulation of multiple molecules such as CAMKII, PKA, JNK, and protein phosphatase 2B (PP2B) . Additionally, this compound has been found to exert protective effects against traumatic brain injury by reducing neuronal apoptosis and inhibiting lipid peroxidation .
Molecular Mechanism
The molecular mechanism of this compound involves its action as a non-competitive antagonist of the AMPA receptor. By binding to a site distinct from the glutamate binding site, this compound inhibits the receptor’s activity, leading to decreased neuronal excitation . This inhibition is achieved through negative allosteric modulation, which prevents the receptor from undergoing the conformational changes necessary for ion channel opening . This compound’s effects on gene expression include the modulation of signaling pathways that regulate the phosphorylation of AMPA receptor subunits .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound have been observed to change over time. This compound is stable and maintains its efficacy in reducing seizure activity over extended periods. In studies involving epileptic rats, this compound effectively inhibited spontaneous seizure activities and maintained its neuroprotective effects without negatively impacting cognitive abilities . Additionally, this compound has been shown to resolve status epilepticus within 24 hours in patients with inflammatory or autoimmune etiologies .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. In a rat model of chronic epilepsy, fully adherent rats demonstrated a significant reduction in seizure frequency with this compound treatment, while nonadherent rats experienced an increase in seizure frequency . High doses of this compound have been associated with adverse effects such as vomiting and decreased activity in beagle dogs . The therapeutic index of this compound is narrow, and optimal dosing strategies are essential to maximize its efficacy while minimizing adverse effects .
Metabolic Pathways
This compound is primarily metabolized by the cytochrome P450 enzymes CYP3A4 and CYP3A5 through oxidative metabolism and sequential glucuronidation . The drug is highly metabolized in the liver, and its metabolites are not pharmacologically active . The metabolic pathways of this compound involve interactions with enzymes that regulate its biotransformation and elimination .
Transport and Distribution
This compound is rapidly absorbed after oral ingestion, with a bioavailability of 100% and a volume of distribution of 1.1 L/kg . It is extensively bound to plasma proteins, primarily α1-acid glycoprotein and albumin . This compound undergoes extensive metabolism in the liver, and less than 0.12% of the administered dose is excreted unchanged in the urine . The drug is widely distributed throughout tissues, and its pharmacokinetics are influenced by the presence of enzyme-inducing antiseizure medications .
Subcellular Localization
The subcellular localization of this compound is primarily associated with its target, the AMPA receptor, which is located on the postsynaptic membranes of neurons . This compound’s activity is influenced by its ability to bind to the AMPA receptor and inhibit its function. The drug’s localization to specific subcellular compartments is essential for its therapeutic effects in reducing neuronal excitation and preventing seizures .
Métodos De Preparación
La síntesis de perampanel implica varios pasos, comenzando con la protección del grupo hidroxilo utilizando un grupo protector resistente a los álcalis como dihidropiranilo o tritilo . El intermedio se somete entonces a diversas condiciones de reacción, incluido el uso de ácido p-toluensulfónico monohidratado y dihidropirano, para obtener el producto final . Los métodos de producción industrial suelen implicar cromatografía líquida de alta resolución para la cuantificación y validación de this compound en muestras de plasma .
Análisis De Reacciones Químicas
Perampanel se somete a varios tipos de reacciones químicas, incluida la oxidación, la reducción y la sustitución. Los reactivos comunes utilizados en estas reacciones incluyen acetonitrilo, metanol y ácido ortofosfórico . Los principales productos formados a partir de estas reacciones se analizan normalmente mediante cromatografía líquida de alta resolución y detección de fluorescencia .
Aplicaciones Científicas De Investigación
Perampanel tiene una amplia gama de aplicaciones de investigación científica, en particular en los campos de la química, la biología, la medicina y la industria. En medicina, se utiliza como fármaco antiepiléptico para el tratamiento de las crisis parciales refractarias y las crisis tónico-clónicas generalizadas primarias . En la investigación biológica, se estudia this compound por sus propiedades antiinflamatorias y neuroprotectoras, especialmente en el tratamiento del estado epiléptico con etiología inflamatoria sospechada . Además, se utiliza this compound en la investigación farmacológica para estudiar sus efectos sobre el receptor de ácido α-amino-3-hidroxi-5-metil-4-isoxazolopropiónico .
Comparación Con Compuestos Similares
Perampanel es único entre los fármacos antiepilépticos debido a su inhibición selectiva del receptor de ácido α-amino-3-hidroxi-5-metil-4-isoxazolopropiónico . Compuestos similares incluyen otros fármacos antiepilépticos que se dirigen a diferentes receptores, como la levetiracetam y la lamotrigina . A diferencia de estos fármacos, this compound ofrece la comodidad de la administración una vez al día y se ha demostrado que proporciona un control sostenido de las convulsiones en pacientes con epilepsia resistente a los fármacos .
Propiedades
IUPAC Name |
2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile |
Source
|
|---|---|---|
| Details | Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C23H15N3O/c24-15-17-8-4-5-11-20(17)21-14-18(22-12-6-7-13-25-22)16-26(23(21)27)19-9-2-1-3-10-19/h1-14,16H |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
PRMWGUBFXWROHD-UHFFFAOYSA-N |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=CC=C(C=C1)N2C=C(C=C(C2=O)C3=CC=CC=C3C#N)C4=CC=CC=N4 |
Source
|
| Details | Computed by OEChem 2.3.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C23H15N3O |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID80191501 |
Source
|
| Record name | Perampanel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID80191501 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
349.4 g/mol |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Solubility |
Practically insoluble in water. |
Source
|
| Details | From FDA label. | |
| Record name | Perampanel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08883 | |
| 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) | |
Mechanism of Action |
The exact mechanism of action of perampanel in seizures is not yet determined, but it is known that perampanel decreases neuronal excitation by non-competitive ihibition of the AMPA receptor. |
Source
|
| Record name | Perampanel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08883 | |
| 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. |
380917-97-5 |
Source
|
| Record name | Perampanel | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=380917-97-5 | |
| 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 | Perampanel [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0380917975 | |
| 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 | Perampanel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08883 | |
| 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 | Perampanel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID80191501 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate(4:3) | |
| 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 | PERAMPANEL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/H821664NPK | |
| 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. | |
Synthesis routes and methods I
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Retrosynthesis Analysis
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