부산대학교 도서관

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 (K_i= 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 (K_i= 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