The identification, design, and synthesis of a series of novel sulfamide-and urea-based small-molecule antagonists of the protein–protein interaction IL-2/IL-2Rα are described. Installation of a furan carboxylic acid fragment onto a low-micromolar sulfamide resulted in a 23-fold improvement in activity, providing a sub-micromolar, nonpeptidic IL-2 inhibitor (IC50= 0.60 μM).
