We recently reported a common pharmacophore model for thesystem Xc- transporter, an obligate exchanger of glutamate and cystine, implicatedin dysfunctions such as stroke, addiction and glioma. Our initial Structureactivity relationship (SAR) studies indicate that lipophilic groups in the C-5position of the isoxazole increase transporter binding at the expense of GluR2receptor binding (i.e., the AMPA receptor). In addition to complementary sitesfor the alpha amino acid and gamma carboxylate or their functional equivalents,the pharmacophore model indicates the presence of a substantial lipophilicpocket. The developing SAR suggested that for the isoxazole series of analogs,a shorter linker between the carboxylates and lipophilic moiety could lead toenhanced activity. The target molecules designed considered both pi-pi andcation-pi stacking interactions, and novel palladium catalyzed cross-couplingof the hetero benzylic halides was required. We will report on the scope andlimitations of the palladation, which represents a facile solution to thesynthetic challenge, and progress on the SAR for ligands at the System Xc- Transporterwill be discussed.

Testing the pharmacophore model for the system Xc- transporter: One less carbon

239th National Meeting (2010)

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