Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

Abstract

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

“…The EC 50 value for the ATP dose–response curve with a fixed 9f concentration was higher than that for the ATP curve alone (Figure 1). The inhibition profile for 9f was similar to that of A740003, which acts on the allosteric site of P2X7R (Honore et al, 2006; Lopez-Tapia et al, 2015; Karasawa and Kawate, 2016; Park and Kim, 2017).…”

Bio-based Aromatic Amines from Lignin-Derived Monomers

“…In literature, synthesis of 7 from 3,4-dimethoxyaniline ( 5a ) has been described using tetrabutylammonium tribromide in CH 2 Cl 2 /MeOH, but it gave only 30% isolated yield after column chromatography . In order to efficiently prepare 7 from 1a , the bromination therefore needs to be performed in an earlier step.…”

“…3,4-Dialkoxyanilines find application in the preparation of 4-chloro-6,7-dialkoxyquinazoline ( A ) and 2,4-dichloro-6,7-dialkoxyquinazoline ( B ) (Figure ), , intermediates in the preparation of widely used anticancer drugs such as Prazosin, Alfuzosin, Doxazosin, Terazosin, Gefitinib, and Erlotinib (Figure ). − 3,4-Dimethoxyaniline is a chemical used in dyes synthesis, with a price of 10–16 €/kg (1.5–2.5 €/mol), and 3,4-diethoxyaniline finds a niche application in the preparation of Diethofencarb, a fungicide used to prevent Botrytis …”

A Radical-Mediated Approach to the Total Synthesis of Fluorinated Marinoquinoline A and Related Tricyclic and Tetracyclic Congeners

“…16 Subsequent Suzuki-Miyaura coupling with 2-iodoaniline (11) gave 12 in good yield. 13 Formylation with formic acetic anhydride, 17 followed by dehydration with phosphorus oxychloride in the presence of diisopropylamine resulted in the required cyclisation precursor 14 in good yield (Scheme 3).…”

“…Alternatively, use of Suzuki-Miyaura conditions using aryl iodides and commercially available boronic acids, gave the corresponding amine precursors 17e to 17j in good yields. 16 The third approach involved nucleophilic aromatic substitution of a heteroaryl ring with …”