Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships.
Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.
D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016208:Databases, Factual; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D008246:Lysophospholipids; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D000072000:NF-KappaB Inhibitor alpha; D021281:Quantitative Structure-Activity Relationship; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008246:Lysophospholipids; C000606204:NFKBIA protein, human; D049312:Receptors, Lysophospholipid; D013843:Thiazines; D013844:Thiazoles; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D013110:Sphingosine