In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity

Leukotriene B-4 (LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid ( 12-[R]-HETE) have been postulated to contribute to the pathophysiology of i nflammatory diseases. SE 201993, (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4-me thoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, id entified 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 v itro and for anti-inflammatory activity in vivo. SE 201993 competitively an tagonized [(3)-H]-LTB4 binding to intact human neutrophils (K-i = 7.6 nM) a nd to membranes of RBL 2H3 cells expressing the LTB4 receptor (RBL 2H3-LTB4 R; IC50 = 154 nM). This compound demonstrated competitive antagonism of LTB 4- and 12-(R)-HETE-induced Ca2+ mobilization responses in human neutrophils (IC(50)s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca 2+ mobilization in human cultured keratinocytes (IC50 = 61 nM), RBL 2H3-LTB 4R cells (IC50 = 255 nM) and mouse neutrophils (IC50 = 410 nM). SE 201993 s howed weak LTD4-receptor binding affinity (K-i = 1.9 mu M) and inhibited 5- lipoxygenase (IC50 of 3.6 mu M), both in vitro and ex vivo. In vivo, SE 201 993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produc ed dose-related, long lasting topical anti-inflammatory activity against th e fluid and cellular phases of arachidonic acid-induced mouse ear inflammat ion (ED50 of 580 mu g/ear and 390 mu g/ear, respectively). Similarly, anti- inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50 of 770 and 730 mu g/ear, respectively, against the fluid and cellular phases). These results indicate that SE 2019 93 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inf lammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.