| 论文题目: | Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability |
| 作者: | Xie, X; Zheng, YG ; Chen, H ; Li, J ; Luo, RH ; Chen, L; Zheng, CB ; Zhang, SR ; Peng, PF ; Ma, DKT; Yang, LM ; Zheng, YT; Liu, H; Wang, J |
| 联系作者: | zhengyt@mail.kiz.ac.cn |
| 发表年度: | 2022 |
| DOI: | doi: 10.1021/acs.jmedchem.2c01383 |
| 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 FDA; however, serious side effects limited its clinical use. Herein, 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 Cmax and AUC0-infinity and improved oral bioavail-ability 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 |
| 刊物名称: | Journal of Medicinal Chemistry |
| 论文出处: | https://doi.org/10.1021/acs.jmedchem.2c01383 |
| 影响因子: | 8.039(2021IF) |
