Author/Authors :
Shifeng Pan، نويسنده , , Zhi-Yuan Mi، نويسنده , , Charles Pally، نويسنده , , Christian Beerli، نويسنده , , Alice Chen، نويسنده , , Danilo Guerini، نويسنده , , Klaus Hinterding، نويسنده , , Barbara Nuesslein-Hildesheim، نويسنده , , Tove Tuntland، نويسنده , , Sophie Lefebvre، نويسنده , , Yi Liu، نويسنده , , Wenqi Gao، نويسنده , , Alan Chu، نويسنده , , Volker Brinkmann، نويسنده , , Christian Bruns، نويسنده , , Markus Streiff، نويسنده , , Catherine Ca، نويسنده ,
Abstract :
FTY720 is an immunomodulator with demonstrated efficacy in a phase II 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 (S1P1) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P1 receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P1-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 S1P1 receptor is sufficient to achieve efficacy in an animal model of transplantation.
