Concentrative nucleoside transporters belong to a class of transmembrane proteins which work to transfer their substrates into or out of the cell and have been shown to be efficacious drug targets. Two highly attractive areas in which they are involved are anti-cancer and anti-viral therapeutics, but there is currently a lack of selective, potent, small molecule inhibitors.A human concentrative nucleoside transporter (hCNT1) pharmacophore was designed using biological data from a testing of commercially available flavones and related compounds (Wang et al. Biochem. Pharmacol. 79:307-20, 2010). The resulting pharmacophore hypothesis was used to search a proprietary database of more than 360,000 compounds and ninety-six compounds were selected for testing. A whole-cell based assay employing [3H]- uridine substrate was used to identify active compounds with novel CNT1 inhibitory activity. Two hit molecules, 58B and 82B of a pyridone scaffold showed moderate in vitro activity with IC50s of 12.9 �M and 16.9 �M, respectively. This is tenfold more potent than the standard non-selective inhibitor, Phlorizin, with a reported IC50 of 210 �M. The hits were selected for optimization. Analogues were synthesized for testing to explore the structure-activity relationship of compounds with the pyridone scaffold.

Design, synthesis, and testing of novel substituted pyridones as human concentrative nucleoside transporter 1 (SLC28a1) inhibitors

247th National Meeting (2014)

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