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Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability

文献类型：期刊论文

作者Xie, Xiong2,4; Zheng, Yu-Gui1,3,6,7; Chen, Huan3; Li, Jian2; Luo, Rong-Hua; Chen, Liang1,2; Zheng, Chang-Bo1,6; Zhang, Shurui2,5; Peng, Panfeng2; Ma, Dakota2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-12-22
卷号65期号:24页码:16526-16540
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c0138316526J
通讯作者Zheng, Yong-Tang(zhengyt@mail.kiz.ac.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Wang, Jiang(jwang@lglab.ac.cn)
英文摘要Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by 21 novel tropane derivatives (6-26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher C-max and AUC(0-infinity) and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection.
WOS关键词HIV ; MARAVIROC ; INHIBITOR ; PHARMACOKINETICS ; UK-427,857 ; RESISTANCE ; EFFICACY ; POTENT
资助项目National Natural Science Foundation of China[91953108] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82060670] ; National Natural Science Foundation of China[22177124] ; National Natural Science Foundation of China[21877118] ; Lingang Laboratory[LG-GG-202204-02] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12000000.] ; Strategic Priority Research Program of the Chinese Academy of Sciences[.] ; Yunnan Key Research and Development Program[202103AC100005] ; Shanghai Municipal Science and Technology Major Project ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120215002] ; Science and Technology Commission of Shanghai Municipality[21S11909300] ; Science and Technology Commission of Shanghai Municipality[19431908100]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000905296600001
源URL[http://119.78.100.183/handle/2S10ELR8/303509]  
专题新药研究国家重点实验室
通讯作者Zheng, Yong-Tang; Liu, Hong; Wang, Jiang
作者单位1.Kunming Med Univ, Yunnan Key Lab Pharmacol Nat Prod, Kunming 650500, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Ctr Biosafety Mega Sci,Key Lab Bioact Peptides Yun, Kunming 650223, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Lingang Lab, Shanghai 200031, Peoples R China
6.Kunming Med Univ, Sch Pharmaceut Sci, Kunming 650500, Peoples R China
7.Guangdong Women & Children Hosp, Dept Pharm, Guangzhou 511400, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Xiong,Zheng, Yu-Gui,Chen, Huan,et al. Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(24):16526-16540.
APA Xie, Xiong.,Zheng, Yu-Gui.,Chen, Huan.,Li, Jian.,Luo, Rong-Hua.,...&Wang, Jiang.(2022).Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability.JOURNAL OF MEDICINAL CHEMISTRY,65(24),16526-16540.
MLA Xie, Xiong,et al."Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability".JOURNAL OF MEDICINAL CHEMISTRY 65.24(2022):16526-16540.

入库方式： OAI收割

来源：上海药物研究所

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