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

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...

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Veröffentlicht in:ACS medicinal chemistry letters 2019-06, Vol.10 (6), p.949-953
Hauptverfasser: Tu, Wangyang, Yang, Fanglong, Xu, Guoji, Chi, Jiangtao, Liu, Zhiwei, Peng, Wei, Hu, Bing, Zhang, Lei, Wan, Hong, Yu, Nan, Jin, Fangfang, Hu, Qiyue, Zhang, Lianshan, He, Feng, Tao, Weikang
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Sprache:eng
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Zusammenfassung: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00114