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

doi:10.1016/j.ejmech.2020.112059

	Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors
	Song, Xiaohan 1,2,4; Sun, Pu 3,4; Wang, Jiang 1,2,4; Guo, Wei 3,4; Wang, Yi 3; Meng, Ling-hua 3,4; Liu, Hong 1,2,4
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2020-03-01
卷号	189 页码:14
关键词	IDO1 inhibitors Immunotherapy Anti-Tumor
ISSN号	0223-5234
DOI	10.1016/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.
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关键词	INDOLEAMINE 2,3-DIOXYGENASE ; TRYPTOPHAN CATABOLISM ; CANCER ; POTENT ; IDO ; IMMUNOTHERAPY ; EPACADOSTAT ; DISCOVERY ; LIGAND
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000518700000025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281173]
专题	中国科学院上海药物研究所
通讯作者	Meng, Ling-hua; Liu, Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike 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.