A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model.
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.
Pan
Shifeng
S
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Mi
Yuan
Y
Pally
Charles
C
Beerli
Christian
C
Chen
Alice
A
Guerini
Danilo
D
Hinterding
Klaus
K
Nuesslein-Hildesheim
Barbara
B
Tuntland
Tove
T
Lefebvre
Sophie
S
Liu
Yi
Y
Gao
Wenqi
W
Chu
Alan
A
Brinkmann
Volker
V
Bruns
Christian
C
Streiff
Markus
M
Cannet
Catherine
C
Cooke
Nigel
N
Gray
Nathanael
N
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000068338:Everolimus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014184:Transplantation, Homologous; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
C517408:AUY 954; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes; D015091:beta-Alanine; D000068338:Everolimus; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus