Chemistry & Biology 2006-11-01

A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model.

Shifeng Pan, Yuan Mi, Charles Pally, Christian Beerli, Alice Chen, Danilo Guerini, Klaus Hinterding, Barbara Nuesslein-Hildesheim, Tove Tuntland, Sophie Lefebvre, Yi Liu, Wenqi Gao, Alan Chu, Volker Brinkmann, Christian Bruns, Markus Streiff, Catherine Cannet, Nigel Cooke, Nathanael Gray

Index: Chem. Biol. 13(11) , 1227-34, (2006)

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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 (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) 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.