Disease relevance of [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

• 2. The objective of this study was to examine the anti-inflammatory mechanisms of LFA703 in ischemia/reperfusion (I/R)-induced leukocyte-endothelium interactions in the colon [1].

High impact information on [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

• Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly [2].
• Differential effect of LFA703, pravastatin, and fluvastatin on production of IL-18 and expression of ICAM-1 and CD40 in human monocytes [3].
• Pravastatin and fluvastatin also induced the production of IL-18, tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in human peripheral blood mononuclear cells (PBMC) in contrast to LFA703 [3].
• It was concluded that LFA703 has the inhibitory effect on an IL-18-initiated immune response without any activation on monocytes [3].
• 4. Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice [4].

Biological context of [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

• Indeed, it was found that LFA703 dose-dependently reduced LFA-1-dependent leukocyte adhesion to mouse endothelial cells in vitro with an IC50 of 3.2 microm [1].
• We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703) [4].

Anatomical context of [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

• 3. First, the inhibitory mechanisms of LFA703 on leukocyte adhesion were investigated in vitro using a mouse CD4+8+ thymocyte cell line [1].

Associations of [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate with other chemical compounds

• Thus, the effects of LFA703 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of IL-18 [3].

Gene context of [(1S,3R,7R,8S,8aR)-8-[2-[(2S,4R)-4-hydroxy-1-[[5-(hydroxymethyl)-6-methoxy-naphthalen-2-yl]methyl]-6-oxo-2-piperidyl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

• LFA703 is a novel statin-derived compound, which potently inhibits lymphocyte function antigen-1 (LFA-1, CD11a/CD18) but does not affect HMG-CoA reductase activity [1].

References