Du, Feng, Wang, Xu, Zhang, Qu, Li, Bian (2019) Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer European journal of medicinal chemistry 182() 111629


Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10-21 nM, hIDO1 IC50 = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation. Copyright © 2019 Elsevier Masson SAS. All rights reserved.