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Pharmacophore-Based Design of Sphingosine 1-phosphate-3 Receptor Antagonists That Include a 3,4-Dialkoxybenzophenone Scaffold

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Drug Research Department, Tokyo Research Laboratories, TOA EIYO Ltd., 2-293-3 Amanuma, Oomiya, Saitama 330-0834, Japan, Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan, and Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Cite this: J. Med. Chem. 2007, 50, 3, 442–454
Publication Date (Web):January 11, 2007
https://doi.org/10.1021/jm060834d
Copyright © 2007 American Chemical Society
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    Abstract

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    Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1−5, the S1P3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner−Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 μM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search.

    *

     To whom correspondence should be addressed. Tel:  +81(48)6477971. Fax:  +81(48)6480078. E-mail:  [email protected].

    †

     TOA EIYO Ltd.

    §

     Chiba University.

    ‡

     National Cardiovascular Center Research Institute.

    Abbreviations:  S1P, sphingosine 1-phosphate; EDG, endothelium differentiation gene; GH score, Güner−Henry score.

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    One hundred seven structures in the database for assessing the GH score and the structures of 36 assayed compounds. All elemental analyses (C, H, N) for synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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