Pan, Shifeng, Mi, Yuan, Pally, Charles, Beerli, Christian, Chen, Alice, Guerini, Danilo, Hinterding, Klaus, Nuesslein-Hildesheim, Barbara, Tuntland, Tove, Lefebvre, Sophie, Liu, Yi, Gao, Wenqi, Chu, Alan, Brinkmann, Volker, Bruns, Christian, Streiff, Markus, Cannet, Catherine, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... http://www.cell.com/chemistry-biology/re... doi:10.1016/j.chembiol.2006.09.017
Additional Information:	can archive post-print (ie final draft post-refereeing)
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez... http://www.cell.com/chemistry-biology/re... doi:10.1016/j.chembiol.2006.09.017
Date Deposited:	14 Dec 2009 14:04
Last Modified:	31 Jan 2013 01:27
URI:	https://oak.novartis.com/id/eprint/135