2-substituted-1-naphthols as potent 5-lipoxygenase inhibitors with topical antiinflammatory activity.
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibit bovine seminal vesicle cyclooxygenase. Structure-activity relationships for these two enzymes are different, implying specific enzyme inhibition rather than a nonspecific antioxidant effect. 2-(Aryl-methyl)-1-naphthols are among the most potent 5-lipoxygenase inhibitors reported (IC50 values generally 0.01-0.2 microM) and show excellent antiinflammatory potency in the mouse arachidonic acid ear edema model. To study the effects of structure on in vitro and in vivo activity, four general features of the molecules were varied: the 2-substituent, the 1-hydroxyl group, substitution on the naphthalene rings, and the 1,2-disubstituted naphthalene unit itself. 2-Benzyl-1-naphthol (5a, DuP 654) shows a very attractive profile of topical antiinflammatory activity and is currently in clinical trials as a topically applied antipsoriatic agent.
Batt
D G
DG
Medical Products Department, E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware 19880-0353.
Maynard
G D
GD
Petraitis
J J
JJ
Shaw
J E
JE
Galbraith
W
W
Harris
R R
RR
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D055598:Chemical Phenomena; D002621:Chemistry; D003872:Dermatitis / Q000188:drug therapy*; D004427:Ear Diseases / Q000139:chemically induced / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D015471:Leukemia, Basophilic, Acute / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D016718:Arachidonic Acid; D001091:Arachidonate Lipoxygenases