Cell adhesion molecules (CAMs) are a group of cell surface proteins involved in mediating adhesion of cells to each other and extracellular matrix proteins, including E-selection, ICAM-1, and VCAM-1. The interaction of CAMs on vascular endothelial cells with their counter-receptors on circulation leukocytes, such as Lewis-X antigens, β1 and β2 integrins, leads to the transmigration of leukocytes to the site of injury. A-2058804 is a potent selective inhibitor of E-selectin and ICAM-1 with IC50 values of 20nM and 25nM, respectively[3]. Treatment of a monolayer of HUVECs with 0.1 μM A-205804 exhibited markedly decreased adhesion of flowing human leukocytic cells (HL60) by 60% as monitored by video microscopy. However, A-205804 did not inhibit human T-cell proliferation in tetanus toxoid or Staphylococcus enterotoxin stimulated proliferation assays at concentrations ranging from 5 to 20μM. In vitro, A-205804 inhibited the proliferation of HUVECs with IC50 value of 152nM[3]. In vivo, oral administration of A-205804 produced A-245346 and A-236934 in the plasma of rat[3]. Treatment C56BL/6 mice with A-205804 at 25~100mg/kg three times a week for two weeks indeed efficiently decrease the expression of E-selection on the endothelial vascular niche cells [4].
作用机制
A-205804 noncovalently bound to a macromolecule or complex in the cell nucleus with a molecular weight greater than 650kDa[5].
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