RESUMEN
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.
Asunto(s)
Amidas/química , Amidas/farmacología , Piridonas/química , Piridonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Concentración 50 Inhibidora , Pirroles/química , Pirroles/farmacología , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , SolubilidadRESUMEN
A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.
Asunto(s)
Anticonvulsivantes/farmacología , Quinazolinonas/farmacología , Receptores AMPA/antagonistas & inhibidores , Sulfonamidas/farmacología , Administración Oral , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos DBA , Modelos Moleculares , Estructura Molecular , Quinazolinonas/administración & dosificación , Quinazolinonas/química , Convulsiones/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models.
Asunto(s)
Quinazolinonas/síntesis química , Receptores AMPA/antagonistas & inhibidores , Sulfonamidas/síntesis química , Administración Oral , Animales , Anticonvulsivantes/farmacología , Unión Competitiva/efectos de los fármacos , Cristalografía por Rayos X , Ratones , Estructura Molecular , Quinazolinonas/química , Quinazolinonas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.
Asunto(s)
Amidas/química , Aminopiridinas/química , Ansiolíticos/química , Péptidos/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Animales , Ansiolíticos/síntesis química , Ansiolíticos/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The nuclear hormone receptor retinoic acid receptor-related-orphan-receptor-gamma t (RORγt) is the key transcription factor required for Th17 cell differentiation and for production of IL-17 family cytokines by innate and adaptive immune cells. Dysregulated Th17 immune responses have been associated with the pathogenesis of several inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. In this article, we describe the in vitro pharmacology of a potent and selective low molecular weight RORγt inhibitor identified after a structure-based hit-to-lead optimization effort. The compound interfered with co-activator binding to the RORγt ligand binding domain and impaired the transcriptional activity of RORγt as evidenced by blocked IL-17A secretion and RORE-mediated transactivation of a luciferase reporter gene. The inhibitor effectively reduced IL-17A production by human naive and memory T-cells and attenuated transcription of pro-inflammatory Th17 signature genes, such as IL17F, IL22, IL26, IL23R, and CCR6. The compound selectively suppressed the Th17/IL-17 pathway and did not interfere with polarization of other T helper cell lineages. Furthermore, the inhibitor was selective for RORγt and did not modify the transcriptional activity of the closely related family members RORα and RORß. Using human keratinocytes cultured with supernatants from compound treated Th17 cells we showed that pharmacological inhibition of RORγt translated to suppressed IL-17-regulated gene expression in keratinocyte cell cultures. Furthermore, in ex vivo immersion skin cultures our RORγt inhibitor suppressed IL-17A production by Th17-skewed skin resident cells which correlated with reduced human ß defensin 2 expression in the skin. Our data suggests that inhibiting RORγt transcriptional activity by a low molecular weight inhibitor may hold utility for the treatment of Th17/IL-17-mediated skin pathologies.
Asunto(s)
Interleucina-17/fisiología , Queratinocitos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Piel/patología , Células Th17/fisiología , Acetatos/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Factor de Transcripción STAT3/fisiología , Transducción de Señal/fisiología , Células Th17/citología , Tiramina/análogos & derivados , Tiramina/farmacologíaRESUMEN
The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.
Asunto(s)
Descubrimiento de Drogas , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Dominio Catalítico , Modelos Animales de Enfermedad , Femenino , Inflamación/metabolismo , Modelos Moleculares , RatasRESUMEN
The T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-γ (RORγt) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORγt inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORγt agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helixâ 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORγt modulators.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Proteínas Adaptadoras Transductoras de Señales/química , Sitios de Unión , Ésteres del Colesterol/química , Cristalografía por Rayos X , Humanos , Hidrocarburos Fluorados/química , Imidazoles/química , Modelos Químicos , Proteínas Nucleares/química , Proteína de Interacción con Receptores Nucleares 1 , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Piridinas/química , Sulfonamidas/química , Sulfonas/química , Agua/químicaRESUMEN
A series of potent quinazolinedione sulfonamide antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor were designed and synthesized. The structure-activity relationships (SAR) and inâ vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N-[7-isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)-induced generalized tonic-clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X-ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.
Asunto(s)
Diseño de Fármacos , Quinazolinonas/química , Receptores AMPA/antagonistas & inhibidores , Administración Oral , Animales , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Electrochoque , Ratones , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Quinazolinonas/administración & dosificación , Quinazolinonas/síntesis química , Quinazolinonas/metabolismo , Receptores AMPA/metabolismo , Convulsiones/tratamiento farmacológico , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.
Asunto(s)
Inflamación/prevención & control , Neovascularización Fisiológica/efectos de los fármacos , Nocicepción/efectos de los fármacos , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Oral , Animales , Diseño de Fármacos , Femenino , Células HEK293 , Humanos , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismoRESUMEN
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist. The compound binds to the ligand binding domain (LBD) of RORγt leading to displacement of a co-activator peptide. We show for the first time that a RORγt inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORγt-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and γδT-cells and attenuated transcription of RORγt target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORγt by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Imidazoles/farmacología , Interleucina-17/antagonistas & inhibidores , Linfocitos Intraepiteliales/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas/farmacología , Células Th17/efectos de los fármacos , Animales , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Línea Celular Tumoral , Femenino , Regulación de la Expresión Génica , Células HEK293 , Humanos , Imidazoles/síntesis química , Interleucina-17/genética , Interleucina-17/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/patología , Cinética , Masculino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Regiones Promotoras Genéticas , Unión Proteica , Piridinas/síntesis química , Pirimidinas/síntesis química , Ratas , Ratas Endogámicas Lew , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Transducción de Señal , Células Th17/inmunología , Células Th17/patologíaRESUMEN
Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with preneoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk.
Asunto(s)
Receptores de Ácido Retinoico/antagonistas & inhibidores , Células Th17/citología , Timo/patología , Animales , Regulación hacia Abajo , Femenino , Expresión Génica , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/genética , Células Th17/metabolismoRESUMEN
Retinoic-acid-related orphan receptorâ γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15â mg kg-1 , lowering IL-17 cytokine production in exâ vivo antigen recall assays.
Asunto(s)
Agonismo Inverso de Drogas , Imidazoles , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Piridinas/síntesis química , Receptores de Ácido Retinoico/agonistas , Triazoles , Animales , Sitios de Unión , Células Cultivadas , Cristalografía por Rayos X , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Interleucina-17/sangre , Estructura Molecular , Unión Proteica/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Ratas , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Genómica/métodos , Animales , Inteligencia Artificial , Técnicas Químicas Combinatorias , Humanos , Biblioteca de PéptidosRESUMEN
[reaction: see text] The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with borane-THF complex leads to fragmentation of the bicycle and the stereoselective formation of an azepinoindole derivative was observed.
RESUMEN
The first synthesis of a rotaxane by solid phase chemistry has been achieved, using the resin bead as a 'Mega' stopper during the synthesis. One of the advantages of this methodology over traditional solution routes include the ability to use mass action to drive the chemistry, without complicating the purification process.
RESUMEN
Functionalized deuterioallylic compounds were efficiently prepared by reaction of the corresponding propargylic derivative with the Schwartz reagent followed by hydrolysis of the adduct with D(2)O. The Z-3-deuterio-2-propenylstannane, prepared in pure form for the first time, is a useful reagent for the preparation of deuterioallylic compounds which cannot be synthesized by hydrozirconation of the corresponding derivatives.
RESUMEN
Fluorescence lifetime (FLT)-based assays have developed to become highly attractive tools in drug discovery. All recently published examples of FLT-based assays essentially describe their use for monitoring enzyme-mediated peptide modifications, such as proteolytic cleavage or phosphorylation/dephosphorylation. Here we report the development of competitive binding assays as novel, inhibitor-centric assays, principally employing the FLT of the acridone dye Puretime 14 (PT14) as the readout parameter. Exemplified with two case studies on human serine proteases, the details of the rationale for both the design and synthesis of probes (i.e., active site-directed low-molecular-weight inhibitors conjugated to PT14) are provided. Data obtained from testing inhibitors with the novel assay format match those obtained with alternative formats such as FLT-based protease activity and time-resolved fluorescence resonance energy transfer-based competitive binding assays.
Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores de Proteasas/química , Espectrometría de Fluorescencia/métodos , Acridonas/química , Unión Competitiva , Tampones (Química) , Dominio Catalítico , Transferencia Resonante de Energía de Fluorescencia , Colorantes Fluorescentes/química , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Cinética , Pulmón/enzimología , Conformación Molecular , Peso Molecular , Péptidos/química , Unión Proteica , Proteínas Recombinantes/química , Serina Proteasas/química , Triptasas/químicaRESUMEN
FTY720 (fingolimod, Gilenya®) is a sphingosine 1-phosphate (S1P) receptor modulator that shows significant therapeutic efficacy after oral administration to patients of multiple sclerosis. Because FTY720 does not contain any atom whose PET or SPECT radioisotope would have a half-life compatible with its pharmacokinetic properties, it cannot be used directly for imaging. Instead, we propose BZM055 as a surrogate tracer to study its pharmacokinetics and organ distribution in patients and, given that FTY720 accumulates in myelin sheaths, for myelin imaging. BZM055 (2 a, 2-iodo-FTY720) can be easily radiolabeled with ¹²³I (for SPECT) or ¹²4I (for PET). Not only does it closely mimic the pharmacokinetics and organ distribution of FTY720, but also its affinity, selectivity for S1P receptors, phosphorylation kinetics, and overall physicochemical properties. [¹²³I]BZM055 is currently under development for clinical imaging.
Asunto(s)
Encéfalo/metabolismo , Radioisótopos de Yodo , Vaina de Mielina/metabolismo , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Humanos , Radioisótopos de Yodo/química , Cinética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Vaina de Mielina/diagnóstico por imagen , Vaina de Mielina/patología , Fosforilación , Radiografía , Receptores de Lisoesfingolípidos/metabolismoRESUMEN
RATIONALE: Neuropeptide Y (NPY) and its receptors are densely localized in brain regions involved in the mediation and modulation of fear, including the amygdala. Several studies showed that central NPY is involved in the modulation of fear and anxiety. OBJECTIVES: In the present study, we investigated (1) whether intra-amygdala injections of NPY affect the expression of conditioned fear and (2) whether NPY Y1 receptors (Y1R) mediates the effects of these intra-amygdaloid NPY injections. RESULTS: Intra-amygdala NPY injections robustly decreased the expression of conditioned fear measured by conditioned freezing and fear-potentiated startle. These NPY effects were not mimicked by intra-amygdala injections of the Y1R agonists Y-28 or Y-36, and co-infusion of the Y1R antagonist BIBO 3304 did not block the NPY effects. Furthermore, we tested Y1R-deficient mice in conditioned freezing and found no differences between wild type and mutant littermates. Finally, we injected NPY into the amygdala of Y1R-deficient mice. Y1R deficiency had no effect on the fear-reducing effects of intra-amygdala NPY. CONCLUSIONS: These data show an important role of the transmitter NPY within the amygdala for the expression of conditioned fear. Y1R do not appear to be involved in the mediation of the observed intra-amygdala NPY effects suggesting that these effects are mediated via other NPY receptors.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Miedo/efectos de los fármacos , Neuropéptido Y/farmacología , Receptores de Neuropéptido Y/metabolismo , Análisis de Varianza , Animales , Arginina/análogos & derivados , Arginina/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Reacción Cataléptica de Congelación/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Modelos Animales , Neuropéptido Y/deficiencia , Oligodesoxirribonucleótidos Antisentido/farmacología , Fragmentos de Péptidos/farmacología , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Factores de TiempoRESUMEN
The current review will focus on the recent patents for AMPA receptor antagonists and their claims, evidence for their therapeutic effectiveness in the treatment of epilepsy and their potential role in psychiatric and neurodegenerative disorders. It will also highlight the proposed mechanisms of action and the implications thereof for our current understanding of the biomolecular basis of these pathologies. It will conclude with a summary of what we know, but also point out the remaining uncertainties, especially as this relates to the claims in the patent under discussion.