Discovery of Imidazoisoindole Derivatives as Highly Potent and Orally Active Indoleamine-2,3-dioxygenase Inhibitors

作者：Wangyang Tu, Fanglong Yang, Guoji Xu, Jiangtao Chi, Zhiwei Liu, Wei Peng, Bing Hu, Lei Zhang, Hong Wan, Nan Yu, Fangfang Jin, Qiyue Hu, Lianshan Zhang, Feng He, Weikang Tao · 发表于：ACS Medicinal Chemistry Letters · 年份：2019 · DOI：10.1021/acsmedchemlett.9b00114 · 被引用次数：26 · 研究领域：Tryptophan and brain disorders、Bipolar Disorder and Treatment、Pharmacological Receptor Mechanisms and Effects

A novel series of imidazoisoindoles were identified as potent indoleamine-2,3-dioxygenase (IDO) inhibitors. Lead optimization toward improving potency and eliminating CYP inhibition resulted in the discovery of lead compound 25, a highly potent IDO inhibitor with favorable pharmacokinetic properties. In the MC38 xenograft model in hPD-1 transgenic mice, 25 in combination with the anti-PD-1 monoclonal antibody ( SHR-1210 ) achieved a synergistic antitumor effect superior to each single agent.