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

Suwen Hu; Quan Gu; Zhilong Wang; Zhiyong Weng; Yunrui Cai; Xiaowu Dong; Yongzhou Hu; Tao Liu; Xin Xie

doi:10.1016/j.ejmech.2013.11.013

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

Eur J Med Chem. 2014 Jan:71:259-66. doi: 10.1016/j.ejmech.2013.11.013. Epub 2013 Nov 19.

Authors

Suwen Hu¹, Quan Gu¹, Zhilong Wang², Zhiyong Weng¹, Yunrui Cai¹, Xiaowu Dong¹, Yongzhou Hu¹, Tao Liu³, Xin Xie⁴

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: Lt601@zju.edu.cn.
⁴ 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.

PMID: 24316669
DOI: 10.1016/j.ejmech.2013.11.013

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.

Keywords: Anti-HIV-1 agent; CCR5 inhibitor; Piperidine-4-carboxamide derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemistry*
Anti-HIV Agents / pharmacology*
CCR5 Receptor Antagonists*
Drug Design*
HIV Infections / drug therapy
HIV-1 / drug effects
Humans
Piperidines / chemistry*
Piperidines / pharmacology*
Receptors, CCR5 / metabolism
Structure-Activity Relationship

Substances

Anti-HIV Agents
CCR5 Receptor Antagonists
Piperidines
Receptors, CCR5