Background and Objective: Indoleamine-2,3-dioxygenase 1 (IDO1), which catalyzes the degradation of
L-tryptophan (L-Trp) to N-formyl kynurenine (NFK) in the first and rate-limiting step of Kynurenine (KYN) pathway
has been identified as a promising therapeutic target for cancer immunotherapy. The small molecule Epacadostat
developed by Incyte Corp is the most advanced IDO1 inhibitor in clinical trials.
Methods: In this study, various amidine derivatives were individually installed as the polar capping group onto the
amino ethylene side chain to replace the sulfamoylamino moiety of Epacadostat to develop novel IDO1 inhibitors. A
series of novel 1,2,5-oxadiazol-3-carboximidamide derivatives were designed, prepared, and evaluated for their
inhibitory activities against human IDO1 enzyme and cellular IDO1.
Results: In vitro human IDO1 enzyme and cellular IDO1 assay results demonstrate that the inhibitory activities of
compound 13a and 13b were comparable to Epacadostat, with the enzymatic IC50 values of 49.37nM and 52.12nM
and cellular IC50 values of 12.34nM and 14.34nM, respectively. The anti-tumor efficacy of 13b is slightly better than
Epacadosta in Lewis Lung Cancer (LLC) tumor-bearing mice model.
Conclusion: 13b is a potent IDO1 inhibitor with therapeutic potential in tumor immunotherapy.