Discovery of Potent Competitive Inhibitors of Indoleamine 2,3-Dioxygenase with in Vivo Pharmacodynamic Activity and Efficacy in a Mouse Melanoma Model

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (I DO). Optimization led to the identification of 5l, which is a potent (HeLa IC50 = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of I DO, as measured by decreased kynurenine levels (> 50%) in plasma and dose dependent efficacy in mice hearing GM-CSF-secreting B16 melanoma tumors.