title: 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.
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopez-Tapia
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Keith A M
authors.initials: KA
authors.lastname: Walker
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Brotherton-Pleiss
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Joanie
authors.initials: J
authors.lastname: Caroon
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Dov
authors.initials: D
authors.lastname: Nitzan
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Lee
authors.initials: L
authors.lastname: Lowrie
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Shelley
authors.initials: S
authors.lastname: Gleason
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Zhao
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Berger
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Debra
authors.initials: D
authors.lastname: Cockayne
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Suttmann
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Fitch
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bourdet
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Rege
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Broadbent
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Dvorak
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Wagner
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Fernando
authors.initials: F
authors.lastname: Padilla
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Loe
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Alam
authors.initials: A
authors.lastname: Jahangir
authors.affiliation: Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: André
authors.initials: A
authors.lastname: Alker
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*
chemical_list: C000599809:1,2-dihydropyridinone; D000814:Aniline Compounds; D058920:Purinergic P2X Receptor Antagonists; D011728:Pyridones; D058486:Receptors, Purinergic P2X7