Piperazinyl-oxadiazoles as selective sphingosine-1-phosphate receptor agonists

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4807-11. doi: 10.1016/j.bmcl.2014.09.003. Epub 2014 Sep 6.

Abstract

The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.

Keywords: Agonist; Lymphopenia; Prodrug; S1P1; S1P3.

MeSH terms

  • Administration, Oral
  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Lymphopenia / chemically induced
  • Lymphopenia / pathology
  • Molecular Structure
  • Oxadiazoles / administration & dosage
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Piperazines / administration & dosage
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Receptors, Lysosphingolipid / agonists*
  • Sphingosine-1-Phosphate Receptors
  • Structure-Activity Relationship

Substances

  • Oxadiazoles
  • Piperazines
  • Receptors, Lysosphingolipid
  • S1PR1 protein, rat
  • Sphingosine-1-Phosphate Receptors
  • piperazine-1,2,4-oxadiazole