Journal
CHEMISTRY & BIOLOGY
Volume 13, Issue 11, Pages 1227-1234Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2006.09.017
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FTY720 is an immunomodulator with demonstrated efficacy in a phase 11 trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (SIP,) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the SIP, receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible. reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.
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