Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P₄-R) agonists

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):537-42. doi: 10.1016/j.bmcl.2011.10.096.
Miguel Guerrero  1 ,  Mariangela Urbano ,  Jian Zhao ,  Melissa Crisp ,  Peter Chase ,  Peter Hodder ,  Marie-Therese Schaeffer ,  Steven Brown ,  Hugh Rosen ,  Edward Roberts
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States.
PMID: 22119461 DOI: 10.1016/j.bmcl.2011.10.096
Abstract

High affinity and selective small molecule agonists of the S1P(4) receptor (S1P(4)-R) may have significant therapeutic utility in diverse disease areas including autoimmune diseases, viral infections and thrombocytopenia. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 3-(2-(2,4-dichlorophenoxy)ethoxy)-6-methyl-2-nitropyridine as a moderately potent and selective S1P(4)-R hit agonist. Design, synthesis and systematic structure-activity relationships study of the HTS-derived hit led to the development of novel potent S1P(4)-R agonists exquisitely selective over the remaining S1P(1-3,5)-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R.

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