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 poten...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (14), p.2347-2350
Hauptverfasser:	Ukita, Tatsuzo, Sugahara, Masakatsu, Terakawa, Yoshihiro, Kuroda, Tooru, Wada, Kazuteru, Nakata, Aya, Kikkawa, Hideo, Ikezawa, Katsuo, Naito, Kazuaki
Format:	Artikel
Sprache:	eng
Schlagworte:	3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Animals Binding, Competitive - drug effects Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cyclic Nucleotide Phosphodiesterases, Type 4 Dose-Response Relationship, Drug Indicators and Reagents Isoquinolines - chemical synthesis Kinetics Lipopolysaccharides - antagonists & inhibitors Lipopolysaccharides - pharmacology Medical sciences Mice Pharmacology. Drug treatments Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - metabolism Phosphodiesterase Inhibitors - pharmacology Quinolines - chemical synthesis Rolipram - metabolism Stereoisomerism Tumor Necrosis Factor-alpha - biosynthesis
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Zusammenfassung:	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-α production in mice. 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-α production in mice.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(03)00438-4