Integrins are transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. The presence of integrins allows rapid and flexible responses to events at the cell surface. Specifically, inflammation results from a series of complex events, including vasodilation, increased vascular permeability, and exudation of liquid and plasma proteins. Adhesion molecules, including E-selectin, ICAM-1, and VCAM-1, are used to recruit sites of circulating leukocyte inflammation. Besides, sialylated Lewis-X antigens on E-selectin and its binding anti receptor leukocytes cause cells to roll on the vascular endothelium. Moreover, LFA-1 and Mac-1 interact with immunoglobulin superfamily members to activate the endothelium. While VLA-4 interacts with blood vessels to activate cell adhesion molecule 1 (VCAM-1). Adhesion molecules are relevant to a variety of pathological conditions including rheumatoid arthritis, Crohn’s disease, radiation pneumonitis, and inflammatory bowel disease. A-205804 is an orally bioavailable, potent and selective lead inhibitor of E-selectin and ICAM-1 expression.
How does A-205804 work on the targets? Let’s study it together. In the beginning, A-205804 is an orally bioavailable, potent and oselective lead inhibitor of E-selectin and ICAM-1 expression (IC50=20 nM and 25 nM, respectively). In addition, A-205804 exhibits cellular toxicities for HUVEC with an IC50 of 152 μM. Meanwhile, A-205804 is an effective inhibitor of cell-cell adhesion in an in vitro flow experiment, demonstrating relevance in a model physiological system. Nonetheless, A-205804 can be used in the research of chronic inflammatory diseases. Finally, A-205804 was effective in reducing in vitro cell-cell adhesion under flow conditions. A monolayer of HUVEC pretreated with 0.1 µM of A-205804 exhibited markedly reduced adhesion of flowing human leukocytic cells (HL60) by 60%. All in all, A-205804 is an orally bioavailable, potent, selective lead inhibitor of E-selectin and ICAM-1 expression.
References:
Stewart AO, et al. J Med Chem. 2001 Mar 15;44(6):988-1002.