Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors.


State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: [Email]


Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23, 25 and 26 showed significant inhibitory activity against hIDO1 (IC50 = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC50 = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t1/2 = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation.


Anti-Tumor,IDO1 inhibitors,Immunotherapy,