Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists

  • Bioorg Med Chem Lett. 2011 Jun 15;21(12):3632-6. doi: 10.1016/j.bmcl.2011.04.097.
Miguel Guerrero  1 ,  Mariangela Urbano ,  Subash Velaparthi ,  Jian Zhao ,  Marie-Therese Schaeffer ,  Steven Brown ,  Hugh Rosen ,  Edward Roberts
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States.
PMID: 21570287 DOI: 10.1016/j.bmcl.2011.04.097
Abstract

Selective S1P(4) receptor antagonists could be novel therapeutic agents for the treatment of influenza Infection in addition to serving as a useful tool for understanding S1P(4) receptor biological functions. 5-(2,5-Dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide was identified from screening the Molecular Libraries-Small Molecule Repository (MLSMR) collection and selected as a promising S1P(4) antagonist hit with moderate in vitro potency and high selectivity against the Other family receptor subtypes (S1P(1-3,5)). Rational chemical modifications of the hit allowed the disclosure of the first reported highly selective S1P(4) antagonists with low nanomolar activity and adequate physicochemical properties suitable for further lead-optimization studies.

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