Design, Synthesis And Biological Evaluation Of Novel Piperidine Derivatives As Potent CCR5Inhibitors

The AIDs, which is caused by human immunodeficiency virus (HIV) infection, was a lethal disease threatening human’s health at present. Despite its effect on reducing the morbidity and mortality of HIV-1-infected individuals, the highly active anti-retroviral therapy (HAART) suffered from frequent adverse events, especially toxicity, as well as the development of drug resistance. Thus, there has been a clear demand for the exploration of novel drugs with an alternative mechanism to cure HIV. Viral entry inhibitors are a validated target for controlling HIV-1infection. The researchers found chemokine receptor5(CCR5) serves as one of the major viral binding sites. This fact inspired many researchers to develop CCR5antagonists which not only display significant activity against HIV-1infection, but also conquer the limitation of HAART.In this research, TAK-220was chosen as the lead compound. As a result of intensified efforts, two series of piperidin-4-carboxyl and piperidin-1-cyclohexyl derivatives, totally44new compounds, were designed, synthesized and biologically evaluated for their CCR5antagonistic activities based on calcium mobilization assay. The results showed that the compounds2-89、2-96、2-97and2-98(IC50=4.78,5.67,2.04and1.35nM, respectively)were better than that of maraviroc (IC50=11.38nM).6of the piperidin-4-carboxyl derivatives were tested for their anti-HIV-1activities. And some of them were found to have potent anti-HIV-1activities. The above results will provide experimental clues for designing of novel CCR5antagonists.