| Autor: |
Sarau, H. M., Foley, J. J., Schmidt, D. B., Martin, L. D., Webb, E. F., Tzimas, M. N., Breton, J. J., Chabot-Fletcher, M., Underwood, D. C., Hay, D. W. P., Kingsbury, W. D., Chambers, P. A., Pendrak, I., Jakas, D. R., Sathe, G. M., Horn, S. Van, Daines, R. A., Griswold, D. G. |
| Zdroj: |
Prostaglandins, Leukotrienes and Essential Fatty Acids; July 1999, Vol. 61 Issue: 1 p55-64, 10p |
| Abstrakt: |
Summary Leukotriene B4(LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SB 201993, (E)-3 [[[[6-(2-carboxyethenyl)-5-[lsqb;8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB4, was evaluated as an antagonist of LTB4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SB 201993 competitively antagonized 3-H-LTB4binding to intact human neutrophils (Ki= 7.6 NM) and to membranes of RBL 2H3 cells expressing the LTB4receptor (RBL 2H3-LTB4R; IC50= 154 nM). This compound demonstrated competitive antagonism of LTB4- and 12-(R)-HETE-induced Ca2+mobilization responses in human neutrophils (IC50s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca2+mobilization in human cultured keratinocytes (IC50= 61 nM), RBL 2H3-LTB4R cells (IC50= 255 nM) and mouse neutrophils (IC50= 410 nM). SB 201993 showed weak LTD4-receptor binding affinity (Ki= 1.9 μM) and inhibited 5-lipoxygenase (IC50of 3.6 mM), both in vitro and ex vivo. In vivo, SB 201993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED50of 580 μg/ear and 390 μg/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50of 770 and 730 mg/ear, respectively, against the fluid and cellular phases). These results indicate that SB 201993 blocks the actions of LTB4and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models. Copyright 1999 Harcourt Publishers Ltd |
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