Stereochemistry-activity relationship of orally active tetralin S1P agonist prodrugs

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2264-9. doi: 10.1016/j.bmcl.2010.02.006. Epub 2010 Feb 6.

Abstract

Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (-)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / pharmacology*
  • Lymphopenia / chemically induced
  • Mice
  • Models, Molecular
  • Multiple Sclerosis / drug therapy
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / metabolism*
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / metabolism
  • Tetrahydronaphthalenes / pharmacokinetics
  • Tetrahydronaphthalenes / pharmacology*

Substances

  • Immunosuppressive Agents
  • Prodrugs
  • Receptors, Lysosphingolipid
  • Tetrahydronaphthalenes
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • tetralin