ABSTRACT
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.
Subject(s)
Cognitive Dysfunction , Receptors, N-Methyl-D-Aspartate , Rats , Animals , Receptors, N-Methyl-D-Aspartate/metabolism , Hippocampus/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolismABSTRACT
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.
Subject(s)
Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Nucleotidyltransferases/antagonists & inhibitors , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Cells, Cultured , Crystallography, X-Ray , DNA/immunology , DNA/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , High-Throughput Screening Assays/methods , Humans , Immunity, Innate/drug effects , Interferons/immunology , Interferons/metabolism , Macrophages , Models, Molecular , Nucleotides, Cyclic/immunology , Nucleotides, Cyclic/metabolism , Nucleotidyltransferases/immunology , Nucleotidyltransferases/isolation & purification , Nucleotidyltransferases/metabolism , Primary Cell Culture , Recombinant Proteins/immunology , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolismABSTRACT
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.
Subject(s)
Nitrogen Oxides/chemistry , Amines/chemistry , Catalysis , Copper/chemistry , Cycloaddition Reaction , Ethers/chemistry , Oxidation-ReductionABSTRACT
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.
Subject(s)
Copper/chemistry , Nitrogen Oxides/chemistry , Organometallic Compounds/chemistry , Amines/chemistry , Catalysis , Ethers/chemistry , Molecular Structure , Nitrogen Oxides/chemical synthesis , Oxidation-Reduction , StereoisomerismABSTRACT
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.