Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: discovery of potent S1P1 receptor agonists

Bioorg Med Chem Lett. 2005 Aug 1;15(15):3568-72. doi: 10.1016/j.bmcl.2005.05.097.

Abstract

The novel immunosuppressant FTY720 has been demonstrated to elicit immunomodulating effects via interaction with the G-protein coupled receptor S1P(1). FTY720 induced agonism at the S1P(3) receptor, however, has been shown to result in mild bradycardia, a minor side-effect of initial FTY720 therapy. This report describes the synthesis of several potent 4(5)-phenylimidazole-based S1P(1) receptor agonists that are accompanied by poor agonist activity at S1P(3). For instance, compound 20 displayed an EC(50)=4.7+/-1.3 nM at the S1P(1) receptor and EC(50)=780+/-1.3 nM at the S1P(3) receptor using a [gamma-(35)S]GTP-binding assay as compared to phospho-FTY720 (S1P(1): EC(50)=1.3+/-1.3nM, S1P(3): EC(50)=2.0+/-2.4 nM).

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Bradycardia / drug therapy
  • CHO Cells
  • Cricetinae
  • Fingolimod Hydrochloride
  • Immunosuppressive Agents / chemical synthesis*
  • Immunosuppressive Agents / pharmacology
  • Lethal Dose 50
  • Lysophospholipids / chemical synthesis*
  • Lysophospholipids / pharmacology
  • Propylene Glycols / chemical synthesis*
  • Propylene Glycols / pharmacology
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / chemical synthesis
  • Sphingosine / pharmacology
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Immunosuppressive Agents
  • Lysophospholipids
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Fingolimod Hydrochloride
  • Sphingosine