Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3.
Zhen Li, Weirong Chen, Jeffrey J Hale, Christopher L Lynch, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, Stephen A Parent, James Bergstrom, Deborah Card, Michael Forrest, Elizabeth J Quackenbush, L Alexandra Wickham, Hugo Vargas, Rose M Evans, Hugh Rosen, Suzanne Mandala
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.
