Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors.
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.
Kagayama
Kohei
K
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
Morimoto
Tatsuya
T
Nagata
Seigo
S
Katoh
Fumitaka
F
Zhang
Xin
X
Inoue
Naoki
N
Hashino
Asami
A
Kageyama
Kiyoto
K
Shikaura
Jiro
J
Niwa
Tomoko
T
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
D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D007659:Ketones; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D014409:Tumor Necrosis Factor-alpha; C030796:benzylamine