Leukotriene biosynthesis inhibition by aryl and aroyl substituted naphthoquinones.
Naphthoquinones are known to inhibit 5-lipoxygenase. In particular, CGS 8515 (methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino]benzoate) has been studied in detail. However this potent and selective 5-lipoxygenase inhibitor has a short duration of action and poor bioavailability. To improve the duration of action we have prepared a series of carbon substituted naphthoquinones. Several members of this series have demonstrated potent in vitro inhibition of 5-LO (IC50's less than 10(-6) M) and at doses of 1 mg/kg iv completely inhibited LTB4 production measured in ex vivo A23187-stimulated blood from dogs. The duration of action measured by the ex vivo assay was improved up to threefold over CGS 8515.
Roland
D M
DM
Research Department, CIBA-GEIGY Corp., Summit, NJ 07901.
Macchia
W M
WM
Grim
K S
KS
Kimble
E F
EF
White
D H
DH
Kowalski
T J
TJ
D000818:Animals; D001682:Biological Availability; D000001:Calcimycin / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006207:Half-Life; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D011863:Radioimmunoassay; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D007975:Leukotriene B4; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine