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Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors

文献类型：期刊论文

作者Song, Xiaohan2,3,4; Sun, Pu1,4; Wang, Jiang2,3,4; Guo, Wei1,4; Wang, Yi1; Meng, Ling-hua1,4; Liu, Hong2,3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-03-01
卷号189页码:14
关键词IDO1 inhibitors Immunotherapy Anti-Tumor
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.112059
通讯作者Meng, Ling-hua(lhmeng@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDOL, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase Ill clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti -tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti -tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23, 25 and 26 showed significant inhibitory activity against hIDO1 (IC50 = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC50 = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t(1/2) = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation. (C) 2020 Elsevier Masson SAS. All rights reserved.
WOS关键词INDOLEAMINE 2,3-DIOXYGENASE ; TRYPTOPHAN CATABOLISM ; CANCER ; POTENT ; IDO ; IMMUNOTHERAPY ; EPACADOSTAT ; DISCOVERY ; LIGAND
资助项目National Program on Key Basic Research Project (973 Program) of China[2015CB910304] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[21402226]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000518700000025
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/281173]  
专题新药研究国家重点实验室
通讯作者Meng, Ling-hua; Liu, Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Song, Xiaohan,Sun, Pu,Wang, Jiang,et al. Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,189:14.
APA Song, Xiaohan.,Sun, Pu.,Wang, Jiang.,Guo, Wei.,Wang, Yi.,...&Liu, Hong.(2020).Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,189,14.
MLA Song, Xiaohan,et al."Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 189(2020):14.

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来源：上海药物研究所

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