Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2

doi:10.1021/acsmedchemlett.1c00113

	Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2
	Che, Jinxin 1; Wang, Zhilong 2; Shen, Zheyuan 1; Zhuang, Weihao 1; Ying, Huazhou 1; Hu, Yongzhou 1; Hu, Youhong 3,4; Xie, Xin 2,4; Dong, Xiaowu 1,5,6
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	2021-05-13
卷号	12 期号:5 页码:836-845
关键词	cancer metastasis CXCR1 CXCR2 selectivity antagonist 1,5-dihydro-4H-imidazol-4-one
ISSN号	1948-5875
DOI	10.1021/acsmedchemlett.1c00113
通讯作者	Hu, Youhong(yhhu@simm.ac.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn)
英文摘要	CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) have been demonstrated to have critical roles in cancer metastasis. Because they share high homology sequences, it is still unclear how to design selective CXCR1 or CXCR2 antagonists. Based on a pharmacophore model we built, compound 2 bearing a 1,5-dihydro-4H-imidazol-4-one scaffold was identified as a selective CXCR2 antagonist with a low CXCR1 antagonism preference. Further optimization and structure-activity relationship studies led to compound C5 that overcame the disadvantages of compound 2 and performed with higher selectivity. It showed excellent oral bioavailability and in vitro anticancer metastasis activity. Further dynamic simulation of the molecular protein complex showed that the amino acid residue K320 of CXCR2 contributed most to the selectivity of C5. This study provides important clues for the design of new CXCR2 selective antagonists, and C5 can be a molecular tool for investigating the difference in the biological function of CXCR1 and CXCR2.
资助项目	National Natural Science Foundation of China[81973172] ; National Natural Science Foundation of China[82003579] ; China Postdoctoral Science Foundation[2019M652123] ; Zhejiang Provincial Natural Science Foundation of China[LR21H300003] ; Zhejiang Provincial Natural Science Foundation of China[LQ21H300005]
WOS关键词	OPTIMIZATION ; CANCER ; SERIES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000651790900024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297249]
专题	中国科学院上海药物研究所
通讯作者	Hu, Youhong; Xie, Xin; Dong, Xiaowu
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Hangzhou 310058, Peoples R China 2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Laborarory Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310058, Peoples R China 5.ZhejiangUniv, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China 6.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
推荐引用方式 GB/T 7714	Che, Jinxin,Wang, Zhilong,Shen, Zheyuan,et al. Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2[J]. ACS MEDICINAL CHEMISTRY LETTERS,2021,12(5):836-845.
APA	Che, Jinxin.,Wang, Zhilong.,Shen, Zheyuan.,Zhuang, Weihao.,Ying, Huazhou.,...&Dong, Xiaowu.(2021).Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2.ACS MEDICINAL CHEMISTRY LETTERS,12(5),836-845.
MLA	Che, Jinxin,et al."Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2".ACS MEDICINAL CHEMISTRY LETTERS 12.5(2021):836-845.