Lipophilic Ligand Efficiency-Monitored Discovery of Potent, Achiral, and Bioavailable Apo-IDO1 Inhibitors.

The indoleamine 2,3-dioxygenase 1 (IDO1) enzyme promotes an immunosuppressive microenvironment and disrupts natural antitumor immune response in cancer cells. IDO1 inhibition has been a target of multiple cancer immunotherapy efforts and is of interest to autoimmune and neurodegenerative disease therapeutic areas. While the first-generation holo-IDO1 inhibitor, epacadostat, did not demonstrate sufficient response in the phase III ECHO-301 trial, multiple next-generation inhibitors and combination therapy clinical trials are ongoing. Herein, we describe our IDO1 inhibitor discovery and optimization effort, in which the lipophilic ligand efficiency index was used to track and guide drug-likeness, minimize entropic penalty, and deliver novel, potent, selective, and orally bioavailable apo-IDO1 inhibitors. Compounds in this class have the potential for an improved pharmacodynamic response and thus are potentially attractive clinical candidates. Our lead molecules are achiral and can be easily synthesized on a large scale in several synthetic steps.