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Open AccessArticle

Design, Synthesis and Biological Evaluation of Phenyl Urea Derivatives as IDO1 Inhibitors

1
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Orazio Nicolotti
Molecules 2020, 25(6), 1447; https://doi.org/10.3390/molecules25061447
Received: 3 March 2020 / Revised: 18 March 2020 / Accepted: 19 March 2020 / Published: 23 March 2020
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Enzyme Inhibitors)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives i12, i23, i24 as showed potent IDO1 inhibition, with IC50 values of 0.1–0.6 μM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound i12 within IDO1. Compound i12 was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound i12 had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound i12 orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of i12-treated mice showed no obvious reduction compared with the control group. Overall, compound i12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents. View Full-Text
Keywords: indoleamine 2,3-dioxygenase 1; tryptophan metabolism; immunotherapeutic target; anti-tumor; IDO1 inhibitor indoleamine 2,3-dioxygenase 1; tryptophan metabolism; immunotherapeutic target; anti-tumor; IDO1 inhibitor
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Zhou, C.; Lai, F.; Sheng, L.; Chen, X.; Li, Y.; Feng, Z. Design, Synthesis and Biological Evaluation of Phenyl Urea Derivatives as IDO1 Inhibitors. Molecules 2020, 25, 1447.

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