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

  • J Med Chem. 2005 Oct 6;48(20):6169-73. doi: 10.1021/jm0503244.
Zhen Li  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratory, Rahway, New Jersey 07065, USA. [email protected]
PMID: 16190743 DOI: 10.1021/jm0503244
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.

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