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Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

2015; American Chemical Society; Volume: 58; Issue: 21 Linguagem: Inglês

10.1021/acs.jmedchem.5b00365

1520-4804

Francisco Lopez‐Tapia, Keith A. M. Walker, Christine Brotherton‐Pleiss, Joanie Caroon, Dov Nitzan, Lee Lowrie, Shelley Gleason, Shu-Hai Zhao, Jacob Berger, Debra A. Cockayne, Deborah Phippard, Rebecca Suttmann, William L. Fitch, David L. Bourdet, Pankaj D. Rege, Xiaojun Huang, Scott Broadbent, Charles A. Dvorak, Jiang Zhu, Paul Wagner, Fernando Padilla, Brad Loe, Alam Jahangir, André Alker,

Pneumocystis jirovecii pneumonia detection and treatment

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.