Novel Series of Dihydropyridinone P2X7 Receptor Antagonists

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.