Syntheses of glucose analogues of E5564 as a highly potent anti-sepsis drug candidate.
Glucose analogues 5 and 9 of E5564 were synthesized, and their LPS-antagonistic activities were measured. The inhibitory activities (IC50) on LPS-induced TNFalpha production of these two compounds towards human whole blood cells were 0.06 and 0.83 nM, respectively. Inhibitory doses (ID50) of compounds 5 and 9 on TNFalpha production induced by coinjection of galactosamine and LPS in C3H/HeN mice in vivo were measured and were 0.55 and <0.20 mg/kg, respectively. And also C3H/HeN mice preinjected with compounds 5 and 9 were protected from lethality induced by coinjection of galactosamine and LPS; out of eight mice preinjected with 1 mg/kg of the compounds, one-six and three of eight mice were protected, respectively.
Shiozaki
Masao
M
Chemistry Department, Chemtech Labo., Inc., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan. shioza@shina.sankyo.co.jp
Doi
Hiromi
H
Tanaka
Daisuke
D
Shimozato
Takaichi
T
Kurakata
Shin-ichi
S
D000818:Animals; D004926:Escherichia coli / Q000737:chemistry / Q000378:metabolism; D005947:Glucose / Q000031:analogs & derivatives*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018805:Sepsis / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C404742:E5564; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose