Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives
| Autor: | M. Kruseman, Brad Loe, G. H. Jones, Doreen A. Spires, P. J. Maloney, A. H. Berks, D. V. K. Murthy, R. A. Simpson, M. C. Venuti, John M. Young |
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| Rok vydání: | 1986 |
| Předmět: |
Tetrahydronaphthalenes
Stereochemistry Neutrophils Administration Topical Ether Arachidonic Acids Pharmacology Naphthalenes Arachidonate Lipoxygenases chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Drug Discovery Structure–activity relationship Bioassay Animals Edema Humans Psoriasis Lipoxygenase Inhibitors Arachidonic Acid Aryl Biological activity Ornithine Decarboxylase Inhibitors Quinone Oxygen chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Lipophilicity Molecular Medicine Biological Assay Female |
| Zdroj: | Journal of medicinal chemistry. 29(8) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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