Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors

• Published in: European journal of medicinal chemistry 2023-03, Vol.250, p.115217-115217, Article 115217
• Main Authors: Ye, Ke, Wang, Kaizheng, Wang, Tianyu, Tang, He, Wang, Lin, Zhang, Wanheng, Jiang, Sheng, Zhang, Xiangyu, Zhang, Kuojun
• Format: Article
• Language: English
• Subjects: Animals; Antitumor efficacy; Enzyme Inhibitors - chemistry; HeLa Cells; Humans; IDO1; IDO1 inhibitor; Indoleamine-Pyrrole 2,3,-Dioxygenase; Oncology immunotherapy; Oxadiazoles - chemistry; Rats; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115217

Indoleamine 2,3-dioxygenase-1 (IDO1) has been considered as an attractive target for oncology immunotherapy due to its immunosuppressive effects on the tumor microenvironment. The most advanced IDO1 inhibitor epacadostat in combination with anti-PD-1 antibody failed to show desirable objective response. Epacadostat is now reevaluated in phase III clinical trials, but its pharmacokinetic (PK) properties are unsatisfactory. To further unravel the antitumor efficacy of IDO1 inhibitors, we designed a series of epacadostat analogues by introducing various urea-containing side chains. In particular, the most active compound 3 showed superior inhibitory potency against recombinant hIDO1 and hIDO1 in HeLa cells induced by interferon γ (IFNγ) relative to epacadostat (3, biochemical hIDO1 IC50 = 67.4 nM, HeLa hIDO1 IC50 = 17.6 nM; epacadostat, biochemical hIDO1 IC50 = 75.9 nM, HeLa hIDO1 IC50 = 20.6 nM). Moreover, compound 3 exhibited improved physicochemical properties and rat PK profile with better oral exposure and bioavailability compared with epacadostat. Importantly, this compound exhibited comparable antitumor efficacy with epacadostat in LLC syngeneic xenograft models. Hence, compound 3 represents a promising lead compound for discovery of more effective IDO1 inhibitors. [Display omitted] •A series of novel and potent IDO1 inhibitors were identified.•Compound 3 showed better inhibitory activity against IDO1 than that of epacadostat.•Compound 3 showed a desirable pharmacokinetic (PK) profile.•Compound 3 exhibited excellent antitumor efficacy in LLC xenograft models.