Design and synthesis of 6-methylpyridin-2-one derivatives as novel and potent GluN2A positive allosteric modulators for the treatment of cognitive impairment.

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.

Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.

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.

Functional-group-tolerant catalytic migratory oxidative coupling of nitrones.

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.

Catalytic migratory oxidative coupling of nitrones through an outer-sphere C(sp3)-H activation process.

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.

Catalytic migratory oxidative coupling of nitrones.

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 C═N 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.