| In vitro: |
| J Pharmacol Exp Ther. 2009 Oct;331(1):54-64. | | Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro.[Pubmed: 19592667] | Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol in inflammatory lung injury.
METHODS AND RESULTS:
In this study, we examined the therapeutic potential of several novel 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol analogs to reduce vascular leak. Similar to S1P and 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol, the (R)- and (S)-enantiomers of 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol analogs demonstrate a wider protective concentration range in vitro (1-50 microM) and greater potency than either S1P or 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol. In contrast to 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol-induced EC barrier enhancement, S1P and the 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via G(i)-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts).
CONCLUSIONS:
These results demonstrate the capacity for 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo. |
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