Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity.
Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice. suggesting that 5k would be a promising drug candidate for the treatment of TNF-alpha associated diseases including septic shock.
Hanano
T
T
Drug Discovery Laboratories, Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd., Saitama, Japan. hanano@welfide.co.jp
Adachi
K
K
Aoki
Y
Y
Morimoto
H
H
Naka
Y
Y
Hisadome
M
M
Fukuda
T
T
Sumichika
H
H
D000818:Animals; D001682:Biological Availability; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016753:Interleukin-10 / Q000819:agonists* / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018121:Receptors, Cytokine / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D008070:Lipopolysaccharides; D010879:Piperazines; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10