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

• We designed and synthesized a series of novel piperidine-4-carboxamide derivatives.
• Two compounds showed similar activity to that of the positive control based on calcium mobilization assay.
• Two compounds displayed nanomolar activity by HIV-1 single cycle antiviral assay.
• The pharmacokinetic properties and cardiovascular safety (hERG) of 16g were evaluated.

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.

16g and 16i showed equivalent inhibitory activity to that of the positive control maraviroc.Figure optionsDownload as PowerPoint slide