title: Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors.
abstract: Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure-activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-alpha production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14 Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. k.kagayama@po.nippon-shinyaku.co.jp
authors.forename: Kohei
authors.initials: K
authors.lastname: Kagayama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Seigo
authors.initials: S
authors.lastname: Nagata
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Katoh
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Naoki
authors.initials: N
authors.lastname: Inoue
authors.forename: Asami
authors.initials: A
authors.lastname: Hashino
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kageyama
authors.forename: Jiro
authors.initials: J
authors.lastname: Shikaura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D001773:Blood Cells / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy; D007659:Ketones; D051379:Mice; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010793:Phthalazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D007659:Ketones; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D014409:Tumor Necrosis Factor-alpha; C030796:benzylamine