Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors

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• 作者：Suwen Hu ; Quan Gu ; Zhilong Wang ; Zhiyong Weng ; Yunrui Cai ; Xiaowu Dong ; Yongzhou Hu ; Tao Liu ; Xin Xie
• 关键词：CCR5 inhibitor ; Anti-HIV-1 agent ; Piperidine-4-carboxamide derivatives
• 刊名：European Journal of Medicinal Chemistry
• 出版年：7 January, 2014
• 年：2014
• 卷：71
• 期：Complete
• 页码：259-266
• 全文大小：382 K

文摘

Based on a putative 鈥榊 shape鈥?pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC₅₀聽=聽25.73聽nM) and 16i (IC₅₀聽=聽25.53聽nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀聽=聽25.43聽nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC₅₀ values of 73.01聽nM and 94.10聽nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.