Novel Series of Dihydropyridinone P2X7 Receptor Antagonists
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- 作者：Francisco Lopez-Tapia ; Keith A. M. Walker ; Christine Brotherton-Pleiss ; Joanie Caroon ; Dov Nitzan ; Lee Lowrie ; Shelley Gleason ; Shu-Hai Zhao ; Jacob Berger ; Debra Cockayne ; Deborah Phippard ; Rebecca Suttmann ; William L. Fitch ; David Bourdet ; Pankaj Rege ; Xiaojun Huang ; Scott Broadbent ; Charles Dvorak ; Jiang Zhu ; Paul Wagner ; Fernando Padilla ; Brad Loe ; Alam Jahangir ; Andr茅 Alker
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：November 12, 2015
- 年：2015
- 卷：58
- 期：21
- 页码：8413-8426
- 全文大小：581K
- ISSN：1520-4804
文摘
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鈥? 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.