Characterization of CGS 8515 as a selective 5-lipoxygenase (5-LO) inhibitor.
1. CGS 8515 selectively inhibited 5-LO (IC50 = 0.1 microM) with negligible effect on CO, 12-LO, 15-LO and TxS at concentrations up to 100 microM. 2. CGS 8515 selectively inhibited A23187-induced formation of 5-LO products in rat and human whole blood with a 20-70 fold separation of effects over the formation of CO products. 3. Ex vivo and in vivo studies with rats showed that CGS 8515, at an oral dose of 2-50 mg/kg, significantly inhibited A23187-induced formation of LTs in whole blood and in the lung. The effect persisted for at least 6 h in the ex vivo blood model. 4. CGS 8515, at oral doses as low as 5 mg/kg, significantly suppressed exudate volume and leukocyte migration in the carrageenan-induced pleurisy and sponge models in the rat.
Ku
E C
EC
CIBA-GEIGY Corp., Summit, New Jersey 07901.
Raychaudhuri
A
A
Ghai
G
G
Kimble
E F
EF
Lee
W H
WH
Colombo
C
C
Dotson
R
R
White
D
D
Oglesby
T D
TD
Wasley
J W
JW
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood*; D001091:Arachidonate Lipoxygenases / Q000097:blood*; D001095:Arachidonic Acids / Q000097:blood; D000001:Calcimycin / Q000494:pharmacology; D002465:Cell Movement; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones / Q000494:pharmacology*; D051381:Rats; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D000001:Calcimycin; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase