Inhibitors of adhesion molecules expression; the synthesis and pharmacological properties of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives.
During a search for novel, orally-active inhibitors of upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), we found a new series of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives to be potent ICAM-1 inhibitors. Of these compounds, N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-N',N'-dimethylsulfamide 7p showed the potent oral inhibitory activities against neutrophil migration in a murine interleukin-1 (IL-1) induced paw inflammation model. The synthesis and structure-activity relationships of these amide derivatives are described.
Tsukuba Research Laboratories, Eisai Co., Ltd, Ibaraki, Japan. t3-kaneko@hhc.eisai.co.jp
Toshihiko
T
Kaneko
Richard S J
RS
Clark
Norihito
N
Ohi
Tetsuya
T
Kawahara
Hiroshi
H
Akamatsu
Fumihiro
F
Ozaki
Atsushi
A
Kamada
Kazuo
K
Okano
Hiromitsu
H
Yokohama
Kenzo
K
Muramoto
Masayoshi
M
Ohkuro
Osamu
O
Takenaka
Seiichi
S
Kobayashi
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D013843:Thiazines; D018799:Intercellular Adhesion Molecule-1