A common theme in the development of novel therapeutic agents is the replacement of problematic functionality. Sphingosine-1-phosphate (S1P) is a phosphoric acid containing lipid that is involved in signaling endothelial differentiation gene (EDG) receptors (25). Koide and co-workers (25) created a pharmacophore using Catalyst that was based on a series of conformera of S1P. The features consisted of a negative and a positive ionizable group, hydrogen-bond acceptor, hydrophobic group, and a shape-based constraint designed to mimic the lipid tail of S1P. The twenty pharmacophores were used to query the ACD database, resulting in 58 hits. Testing of 32 samples (RJ s> revealed two compounds based on a thiazolidine Ho2c^"\ ^°7Hl5
carboxylic acid motif with greater than 30% inhibition h at 10 pM. Further optimization of this series afforded compound 11, which is selective for the EDG-3 receptor subtype.
The discovery of novel noncompetitive AMPA antagonists may provide treatment for patients with severe epilepsy (26). Currently, there are three major classes of noncompetitive AMPA antagonists known, represented by 2,3-benzodiazepines, phthalazine, and quinazolines. Barreca and co-workers used published data on fourteen compounds to construct a pharmacophore with Catalyst that contains two hydrophobic groups, one hydrogen-bond acceptor, and one aromatic ring feature (26). The pharmacophore was used to query the Maybridge database, which, after filtering, resulted in 200 compounds for further consideration. A total of eight compounds were ultimately selected for testing in an anticonvulsant assay. Of these, compound 12 displayed activity comparable to that of the compounds used to construct the pharmacophore model, and represents a novel class of noncompetitive AMPA antagonists that would be suitable for lead optimization.
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