Synthesis and biological activities of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives as PDE4 inhibitors.
A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.
Ukita
Tatsuzo
T
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, 532-8505, Osaka, Japan. t-ukita@tanabe.co.jp
Sugahara
Masakatsu
M
Terakawa
Yoshihiro
Y
Kuroda
Tooru
T
Wada
Kazuteru
K
Nakata
Aya
A
Kikkawa
Hideo
H
Ikezawa
Katsuo
K
Naito
Kazuaki
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis; D020889:Rolipram / Q000378:metabolism; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007202:Indicators and Reagents; D007546:Isoquinolines; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram