Effect of a 5-lipoxygenase (5-LO)/cyclooxygenase (CO) inhibitor, WY-47, 288, on cutaneous models of inflammation.
WY-47,288 (2-[(1-naphthalenyloxy)methyl]quinoline) demonstrated topical antiinflammatory activity in several animal models of skin inflammation. Application of WY-47,288 to mouse ear surfaces inhibited arachidonic acid (ED50 = 0.3 mg/ear) and tetradecanoylphorbol acetate (TPA)-induced inflammation (40% at 1 mg/ear). Administration of WY-47,288 (1 mg/ear) at 30 min and 5 h after TPA reduced ear edema and epidermal proliferation by 50%. WY-47,288 also inhibited oxazolone-induced contact hypersensitivity in mouse ears (ED50 = 0.4 mg/ear) and UVB-induced guinea pig skin erythema (ED50 approximately 0.25 mg/spot). These antiinflammatory effects may be due to inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) since the synthesis of 5-LO and CO products by rat neutrophils and mouse macrophages was dose-dependently reduced by WY-47,288. By contrast, WY-47,288 demonstrated no appreciable inhibition of 12-LO (rabbit platelet), 15-LO (soybean) or phospholipase A2 (human platelet). Furthermore, no systemic adverse effects were observed after topical, parenteral or oral administration of WY-47,288, suggesting that WY-47,288 is a safe topical 5-LO/CO inhibitor for treating skin inflammation.
Carlson
R P
RP
Division of Experimental Therapeutics, Wyeth-Ayerst Research, Princeton, NJ 08543.
O'Neill-Davis
L
L
Calhoun
W
W
Datko
L
L
Musser
J H
JH
Kreft
A F
AF
Chang
J Y
JY
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D004195:Disease Models, Animal; D004423:Ear; D004890:Erythema / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D006168:Guinea Pigs; D007249:Inflammation; D016859:Lipoxygenase Inhibitors; D051379:Mice; D009281:Naphthalenes / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D011832:Radiation Injuries / Q000188:drug therapy / Q000517:prevention & control; D012459:Salicylates / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D014466:Ultraviolet Rays
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D011804:Quinolines; D012459:Salicylates; C059865:WY 47288; D016718:Arachidonic Acid; C045954:RS 43179; D001091:Arachidonate Lipoxygenases; D013755:Tetradecanoylphorbol Acetate