SKF-86002 is a potent inhibitor of p38 MAP kinase with IC50 of 0.5-1 μM and inhibits LPS-induced IL-1 and TNF-α production in human monocytes (IC50 = 1 μM).
SKF-86002 inhibited prostaglandin H2 (PGH2) synthase activity (IC50 120 μM) as well as prostanoid production in rat basophilic leukemia (RBL-1) cells (IC50 70 μM) and its sonicate (IC50 100 μM) and human monocytes (IC50 1 μM). In addition, SKF-86002 inhibited the generation of dihydroxyeicosatetraenoic acid (diHETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) in a high speed supernatant fraction of RBL-1 cells (IC50 10 μM). Cellular production of 5-lipoxygenase products was inhibited by SKF-86002 as measured by leukotriene B4 (LTB4) generation from human neutrophils (IC50 20 μM), leukotriene C4 (LTC4) generation by human monocytes (IC50 20 μM), and 5-HETE production by RBL-1 cells (IC50 40 μM)[3]. Apoptosis induced by stress stimuli activated p38 MAPK, and apoptosis was inhibited bySKF-86002[4]. SKF-86002 blocked superoxide anion production in response to FMLP and reduced adhesion and chemotaxis in response to PAF or FMLP[5]. In human osteoblastic cells (SaOS2) both basal and TNF alpha-stimulated IL6 production were inhibited in a concentration-related manner by SKF-86002but not by indomethacin[6]. In vivo, profile of anti-inflammatory activity of SKF-86002 supports the dual inhibition of arachidonate metabolism as indicated by its activity in inflammation models that are insensitive to selective cyclooxygenase inhibitors. The responses of arachidonic-acid-induced edema in the mouse ear and rat paw, as well as the cell infiltration induced by carrageenan in the mouse peritoneum and by arachidonic acid in the rat air pouch, were inhibited by SKF-86002[3].
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