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Structure-Based Design of 1-Heteroary1-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists

文献类型：期刊论文

作者Peng, Panfeng2,3,4; Chen, Huan1,2; Zhu, Ya2,4; Wang, Zhilong2,3; Li, Jian2,3,4; Luo, Rong-Hua1,2; Wang, Jiang2,3,4; Chen, Liang2,3,4; Yang, Liu-Meng1,2; Jiang, Hualiang2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-11-08
卷号61期号:21页码:9621-9636
ISSN号0022-2623
DOI10.1021/acs.jmedchem.8b01077
文献子类Article
英文摘要CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 angstrom resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 mu M, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.
WOS关键词HIV-INFECTION ; BIOLOGICAL EVALUATION ; DISCOVERY ; POTENT ; INHIBITORS ; MARAVIROC ; AIDS
资助项目National Program on Key Basic Research Project of China[2012CB910704] ; National Program on Key Basic Research Project of China[2015CB910304] ; National Natural Science Foundation[81321092] ; National Natural Science Foundation[91229205] ; National Natural Science Foundation[81102461] ; National Natural Science Foundation[81102483] ; National Natural Science Foundation[81620108027] ; National Natural Science Foundation[21632008] ; National Natural Science Foundation[21402226] ; China Marine Commonweal Research Project[201005022-5] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120161006] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0320163020] ; National S&T Major Projects[2012ZX09301001-007] ; National S&T Major Projects[2009ZX09501-029] ; National S&T Major Projects[2014ZX10005-002]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000449889200015
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/279496]  
专题药物靶标结构与功能中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Wu, Beili; Zheng, Yong-Tang; Liu, Hong
作者单位1.Chinese Acad Sci, Kunming Inst Zool, KIZ CUHK Joint Lab Bioresources & Mol Res Common, Key Lab Bioact Peptides Yunnan Prov,Key Lab Anim, Kunming 650223, Yunnan, Peoples R China;
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Peng, Panfeng,Chen, Huan,Zhu, Ya,et al. Structure-Based Design of 1-Heteroary1-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(21):9621-9636.
APA Peng, Panfeng.,Chen, Huan.,Zhu, Ya.,Wang, Zhilong.,Li, Jian.,...&Liu, Hong.(2018).Structure-Based Design of 1-Heteroary1-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists.JOURNAL OF MEDICINAL CHEMISTRY,61(21),9621-9636.
MLA Peng, Panfeng,et al."Structure-Based Design of 1-Heteroary1-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists".JOURNAL OF MEDICINAL CHEMISTRY 61.21(2018):9621-9636.

入库方式： OAI收割

来源：上海药物研究所

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