Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity

T Hanano; K Adachi; Y Aoki; H Morimoto; Y Naka; M Hisadome; T Fukuda; H Sumichika

doi:10.1016/s0960-894x(00)00128-1

Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity

Bioorg Med Chem Lett. 2000 May 1;10(9):875-9. doi: 10.1016/s0960-894x(00)00128-1.

Authors

T Hanano¹, K Adachi, Y Aoki, H Morimoto, Y Naka, M Hisadome, T Fukuda, H Sumichika

Affiliation

¹ Drug Discovery Laboratories, Pharmaceutical Research Division, Yoshitomi Pharmaceutical Industries, Ltd., Saitama, Japan. hanano@welfide.co.jp

PMID: 10853650
DOI: 10.1016/s0960-894x(00)00128-1

Abstract

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.

MeSH terms

Animals
Biological Availability
Central Nervous System / drug effects
Central Nervous System / metabolism
Dose-Response Relationship, Drug
Female
Interleukin-10 / agonists*
Interleukin-10 / blood
Lipopolysaccharides / pharmacology
Mice
Mice, Inbred BALB C
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics
Piperazines / pharmacology
Rats
Receptors, Cytokine / agonists*
Receptors, Cytokine / antagonists & inhibitors*
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

Lipopolysaccharides
Piperazines
Receptors, Cytokine
Tumor Necrosis Factor-alpha
Interleukin-10