Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses.
1. Two selective inhibitors of arachidonate 5-lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice. 2. The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6 h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin-soaked polyester sponges, were reduced dose-dependently by BW A4C (ED50 = 2.6 mg kg-1) or BW A797C (ED50 = 14.3 mg kg-1). 3. BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50s greater than 100 mg kg-1). 4. Doses of up to 200 mg kg-1 of either BW A4C or BW A797C had no effect on carrageenin-induced oedema in rat paws. 5. BW A4C and BW A797C had little or no effect on carrageenin-induced hyperalgesia in rats or phenyl-benzoquinone-induced writhing in mice. 6. Yeast-induced pyrexia in rats was reduced by both BW A4C (ED50 = 32 mg kg-1) and BW A797C (ED50 = 23 mg kg-1). 7. The accumulation of leucocytes in sponge exudates was reduced dose-dependently by BW A4C (ED50 = 54 mg kg-1) and BW A797C (ED50 = 16.7 mg kg-1). 8. The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti-pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.
Higgs
G A
GA
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Follenfant
R L
RL
Garland
L G
LG
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000208:Acute Disease; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D015232:Dinoprostone; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D007958:Leukocyte Count / Q000187:drug effects; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011458:Prostaglandins E / Q000097:blood; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D011458:Prostaglandins E; D011720:Pyrazoles; D007975:Leukotriene B4; C006358:acetohydroxamic acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D001091:Arachidonate Lipoxygenases; D015232:Dinoprostone