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

  • ACS Med Chem Lett. 2019 Jun 3;10(6):949-953. doi: 10.1021/acsmedchemlett.9b00114.
Wangyang Tu  1 ,  Fanglong Yang  1 ,  Guoji Xu  1 ,  Jiangtao Chi  1 ,  Zhiwei Liu  1 ,  Wei Peng  1 ,  Bing Hu  1 ,  Lei Zhang  1 ,  Hong Wan  1 ,  Nan Yu  1 ,  Fangfang Jin  1 ,  Qiyue Hu  1 ,  Lianshan Zhang  2 ,  Feng He  1  3 ,  Weikang Tao  1  3
Affiliations
  • 1. Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
  • 2. Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu 222047, China.
  • 3. Chengdu Suncadia Medicine Co., Ltd., 88 South Keyuan Road, Chengdu, Sichuan 610000, China.
PMID: 31223453 DOI: 10.1021/acsmedchemlett.9b00114
Abstract

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.

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