Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.

Indoleamine 2,3-dioxygenase-1 (IDO1) 是下一代癌症免疫疗法的潜在靶点。我们描述了两个系列 IDO1 抑制剂的开发，这些抑制剂结合了基于知识的药物设计产生的N-羟基-噻吩-甲脒核心。改进合成化合物的细胞活性和药代动力学 (PK) 特性的结构修饰，包括N-羟基噻吩-2-甲脒核心侧链的延伸，产生了化合物27a，一种有效的 IDO1 抑制剂，其表现出显着 (51% )体内在人 SK-OV-3 卵巢异种移植肿瘤小鼠模型中靶向抑制 IDO1。预计该策略将适用于发现其他 IDO1 抑制剂，用于治疗其他易受 IDO1 调节的疾病。