is phenolic antioxidant with anti-inflammatory and antiplatelet effects and is potentially useful for the treatment of atherosclerosis and type 2 diabetes
AGI-1067 is a novel ASK1 inhibitor. It improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling. Administration of AGI-1067 at dose of 50-150mg/kg, i.p., inhibited the activation of MKKs/p38 MAPK by inhibiting the disassociation of ASK1 and Trx1, which suppressed the AGE‐induced myocyte apoptosis[1]. AGI-1067 is a novel, phenolic, intra- and extracellular antioxidant that inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. It is the metabolically stable monosuccinic acid ester of probucol representing a novel class of orally bioavailable compounds termed vascular protectants. AGI-1067 also exhibits mild antiplatelet properties inhibiting surface expression of various key platelet receptors, the formation of platelet monocyte microparticles and PAR-1 thrombin receptors[2]. AGI-1067 lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. At the cellular level, AGI-1067 inhibited tumor necrosis factor-alpha-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC50 values = 6, 10, and 25 μM, respectively)[3]. In addition, AGI-1067 reduces H(b)A1c, improves fasting plasma glucose, and reduces new-onset diabetes. Pretreatment with 10 μM AGI-1067 increased glucose-stimulated insulin secretion (11 mM) without affecting secretion in basal (3mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7mM and 11mM glucose, but had no effect in 28mM or basal glucose[4].
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