RESUMEN
N-Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel series of GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold. Initial lead compound 1 was discovered through in silico-based screening of virtual ligands with various monocyclic scaffolds. GluN2A PAM activity was increased by introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain. Modification of the aromatic ring led to the identification of potent and brain-penetrant 6-methylpyridin-2-one 17 with a negligible binding activity for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Oral administration of 17 significantly enhanced rat hippocampal long-term potentiation (LTP). Thus, 17 would be a useful in vivo pharmacological tool to investigate complex NMDAR functions for the discovery of therapeutics toward diseases associated with NMDAR dysfunction.
Asunto(s)
Disfunción Cognitiva , Receptores de N-Metil-D-Aspartato , Ratas , Animales , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismoRESUMEN
Outer-sphere redox catalysis is key to efficient C-H activation, which has attracted increased interest in organic chemistry. In this account, we describe a Cu(I) -catalyzed oxidative coupling between nitrones and various ethers or amines as an example. Predictable site-selective C-C bond formation was achieved through activation of the C-H bonds in each coupling partner and the migration of a C-N double bond. Mechanistic studies strongly suggested that the reaction proceeded via an oxonium/iminium cation species as the key intermediate. The mechanistic information allows for future extension of outer-sphere redox catalysis.
Asunto(s)
Cobre/química , Óxidos de Nitrógeno/química , Compuestos Organometálicos/química , Aminas/química , Catálisis , Éteres/química , Estructura Molecular , Óxidos de Nitrógeno/síntesis química , Oxidación-Reducción , EstereoisomerismoRESUMEN
Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.
Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/farmacología , Nucleotidiltransferasas/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Células Cultivadas , Cristalografía por Rayos X , ADN/inmunología , ADN/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Inmunidad Innata/efectos de los fármacos , Interferones/inmunología , Interferones/metabolismo , Macrófagos , Modelos Moleculares , Nucleótidos Cíclicos/inmunología , Nucleótidos Cíclicos/metabolismo , Nucleotidiltransferasas/inmunología , Nucleotidiltransferasas/aislamiento & purificación , Nucleotidiltransferasas/metabolismo , Cultivo Primario de Células , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismoRESUMEN
A copper-catalyzed migratory oxidative-coupling reaction between nitrones and various ethers/amines exhibited high functional-group tolerance. Even in aqueous media, the reaction proceeded efficiently. For practical use of this catalysis, a unique sequential Huisgen cycloaddition was demonstrated. Mechanistic investigations revealed that the reaction proceeded through oxidative catalytic activation of ethers/amines to afford iminium/oxonium intermediates by concurrent dual one-electron abstractions by copper(II) and oxyl radicals.
Asunto(s)
Óxidos de Nitrógeno/química , Aminas/química , Catálisis , Cobre/química , Reacción de Cicloadición , Éteres/química , Oxidación-ReducciónRESUMEN
A Cu(I)-catalyzed migratory oxidative coupling between nitrones and heterocycles or a methylamine is described. Selective C-C bond-formation proceeds through cleavage of two C(sp(3))-H bonds concomitant with CâN double bond-migration. The reaction provides an alternating nitrone moiety, allowing for further synthetically useful transformations. Radical clock studies suggest that the nucleophilic addition of nitrones to an oxidatively generated carbocation is a key step.