Discovery of potent 3, 5-diphenyl-1, 2, 4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3

…, G Chrebet, SA Parent, J Bergstrom…

Index: Li, Zhen; Chen, Weirong; Hale, Jeffrey J.; Lynch, Christopher L.; Mills, Sander G.; Hajdu, Richard; Keohane, Carol Ann; Rosenbach, Mark J.; Milligan, James A.; Shei, Gan-Ju; Chrebet, Gary; Parent, Stephen A.; Bergstrom, James; Card, Deborah; Forrest, Michael; Quackenbush, Elizabeth J.; Wickham, L. Alexandra; Vargas, Hugo; Evans, Rose M.; Rosen, Hugh; Mandala, Suzanne Journal of Medicinal Chemistry, 2005 , vol. 48, # 20 p. 6169 - 6173

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Citation Number: 96

Abstract

A class of 3, 5-diphenyl-1, 2, 4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50= 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.