| Autor: |
Karl W. Mollison, Thomas A. Fey, Donna M. Gauvin, Michael P. Sheets, Morey L. Smith, Melissa Pong, Ruth Krause, Loan Miller, Yat Sun Or, Megumi Kawai, Rolf Wagner, Paul E. Wiedeman, Richard F. Clark, Indrani W. K. Gunawardana, Teresa A. Rhoades, Cynthia L. Henry, Noah P. Tu, Nwe Y. BaMaung, Hana Kopecka, Luping Liu, Qinghua Xie, Benjamin C. Lane, James M. Trevillyan, Kennan Marsh, George W. Carter, Yung-Wu Chen, Gin C. Hsieh, Jay R. Luly |
| Rok vydání: |
1998 |
| Předmět: |
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| Zdroj: |
Current Pharmaceutical Design. 4:367-379 |
| ISSN: |
1381-6128 |
| Popis: |
Abstract: Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid phannacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FKS06) despit_e a severalfold lower potency for inhibiting swine T cells in vitro, consistent-with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30- fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FKS06 in all three species. The potent topical activity and reduced sytemic exposure of ABT- 281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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