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

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 se...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-02, Vol.50 (3), p.442-454
Main Authors: Koide, Yuuki, Uemoto, Kazuhiro, Hasegawa, Takeshi, Sada, Tomoyuki, Murakami, Akira, Takasugi, Hiroshi, Sakurai, Atsuko, Mochizuki, Naoki, Takahashi, Atsuo, Nishida, Atsushi
Format: Article
Language:English
Subjects:
Animals
Benzophenones - chemical synthesis
Benzophenones - chemistry
Benzophenones - pharmacology
Biological and medical sciences
Calcium - metabolism
CHO Cells
Cricetinae
Cricetulus
Databases, Factual
Drug Design
Humans
Medical sciences
Miscellaneous
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Quantitative Structure-Activity Relationship
Receptors, Lysosphingolipid - agonists
Receptors, Lysosphingolipid - antagonists & inhibitors
Stereoisomerism
Transfection
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Summary: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
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060834d