Structure-activity relationships of 6-fluoroquinazolines: dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation.
We synthesized various 6-fluoro-7-(1-piperazino)quinazolines based on the structure of 1 and evaluated their inhibitory activities toward both TNF-alpha production and T cell proliferation responses. Among these compounds, 7a, having the 3,4-(methylenedioxy)phenyl moiety at the C(4)-position of the quinazoline ring, showed both inhibitory activities. Furthermore, the oral treatment with 7a exhibited an anti-inflammatory effect in rats with adjuvant arthritis as well as an inhibitory activity toward LPS-induced TNF-alpha production.
Tobe
Masanori
M
Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, 335-8502, Saitama, Japan.
Isobe
Yoshiaki
Y
Tomizawa
Hideyuki
H
Nagasaki
Takahiro
T
Obara
Fumihiro
F
Hayashi
Hideya
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy; D001402:B-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D003864:Depression, Chemical; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A