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.

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.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dogs
  • Graft Survival
  • Immunosuppressive Agents / chemical synthesis*
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / pharmacology
  • Lymphocyte Count
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Receptors, Lysosphingolipid / agonists*
  • Skin Transplantation
  • Structure-Activity Relationship

Substances

  • Immunosuppressive Agents
  • Oxadiazoles
  • Receptors, Lysosphingolipid