Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives.
On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000287:Administration, Topical; D000818:Animals; D001091:Arachidonate Lipoxygenases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D001681:Biological Assay; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006801:Humans; D016859:Lipoxygenase Inhibitors; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000627:therapeutic use*; D009504:Neutrophils / Q000201:enzymology; D065108:Ornithine Decarboxylase Inhibitors; D010100:Oxygen; D011565:Psoriasis / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000627:therapeutic use
D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D065108:Ornithine Decarboxylase Inhibitors; D013764:Tetrahydronaphthalenes; D016718:Arachidonic Acid; C003020:oxoline; C045954:RS 43179; D001091:Arachidonate Lipoxygenases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D010100:Oxygen