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

Pan, Shifeng and Mi, Yuan and Pally, Charles and Beerli, Christian and Chen, Alice and Guerini, Danilo and Hinterding, Klaus and Nuesslein-Hildesheim, Barbara and Tuntland, Tove and Lefebvre, Sophie and Liu, Yi and Gao, Wenqi and Chu, Alan and Brinkmann, Volker and Bruns, Christian and Streiff, Markus and Cannet, Catherine and Cooke, Nigel Graham and Gray, Nathanael (2006) A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chemistry & Biology, 13 (11). pp. 1227-1234. ISSN 1074-5521

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.

Item Type: Article
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Additional Information: can archive post-print (ie final draft post-refereeing)
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Date Deposited: 14 Dec 2009 14:04
Last Modified: 31 Jan 2013 01:27
URI: https://oak.novartis.com/id/eprint/135

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