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ID: ALA3739255

Journal: J Med Chem

Title: Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Authors: Lopez-Tapia F, Walker KA, Brotherton-Pleiss C, Caroon J, Nitzan D, Lowrie L, Gleason S, Zhao SH, Berger J, Cockayne D, Phippard D, Suttmann R, Fitch WL, Bourdet D, Rege P, Huang X, Broadbent S, Dvorak C, Zhu J, Wagner P, Padilla F, Loe B, Jahangir A, Alker A.

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.

CiteXplore: 26460788

DOI: 10.1021/acs.jmedchem.5b00365