P2X4 receptor antagonists have potential as drugs for the treatment of neuropathic pain and neurodegenerative diseases. In the present study the discovery of phenoxazine derivatives as potent P2X4 antagonists is described. N-Substituted phenoxazine and related acridone and benzoxazine derivatives were synthesized and optimized with regard to their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor. In addition, species selectivity (rat, mouse, human) and receptor subtype selectivity (versus P2X1,2,3,7) were investigated. The most potent P2X4 antagonist of the present series was N-(benzyloxycarbonyl)phenoxazine (26, PSB-12054) with an IC(50) of 0.189 μM and good selectivity versus the other human P2X receptor subtypes. N-(p-Methylphenylsulfonyl)phenoxazine (21, PSB-12062) was identified as a selective P2X4 antagonist that was equally potent in all three species (IC(50): 0.928-1.76 μM). The compounds showed an allosteric mechanism of action. The present study represents the first structure-activity relationship analysis of P2X4 antagonists.

A new catalytic asymmetric Henry reaction has been developed that uses a C(1)-symmetric chiral aminopyridine ligand derived from camphor and picolylamine. A variety of aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes react with nitromethane and other nitroalkanes in the presence of DIPEA (1.0 equiv), Cu(OAc)(2)*H(2)O (5 mol %), and an aminopyridine ligand (5 mol %) to give the expected products in high yields (up to 99 %), moderate-to-good diastereoselectivites (up to 82:18), and excellent enantioselectivities (up to 98 %). The reaction is air-tolerant and has been used in the synthesis of the antifungal agent miconazole.

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus targeting this protein domain may offer a therapeutic strategy to combat current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally occurring nucleotides, small molecules, and nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and provide chemical starting points for future inhibitor development.

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