title: Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors.
abstract: Based on a putative 'Y shape' 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 = 25.73 nM) and 16i (IC₅₀ = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀ = 25.43 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 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Suwen
authors: S
authors: Hu
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Quan
authors: Q
authors: Gu
authors: State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Zhilong
authors: Z
authors: Wang
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Zhiyong
authors: Z
authors: Weng
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Yunrui
authors: Y
authors: Cai
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Xiaowu
authors: X
authors: Dong
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Yongzhou
authors: Y
authors: Hu
authors: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: Lt601@zju.edu.cn.
authors: Tao
authors: T
authors: Liu
authors: State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xxie@mail.shcnc.ac.cn.
authors: Xin
authors: X
authors: Xie
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D019713:Receptors, CCR5
keywords: Anti-HIV-1 agent; CCR5 inhibitor; Piperidine-4-carboxamide derivatives