Discovery and SAR studies of antiviral 4-aminopiperidine derivatives active against SARS-CoV-2

Two related families of 4-aminopiperidine compounds active against SARS-CoV-2 in the micromolar range were discovered by screening the CSIC Chemical library. A medicinal chemistry programme was completed to optimize these series. Seventy-four derivatives of the early hits were synthesized which allowed to develop SAR studies and identify new hit compounds with low micromolar in vitro antiviral activity (EC₉₀ < 2 μM) and improved selectivity indexes in A594-hACE2 cells (from 13- to >28). Compounds which were active against two coronaviruses (SARS-CoV-2 and HCoV-229E) were less effective against the unrelated vesicular stomatitis virus (VSV), suggesting certain selectivity for coronaviruses. Several hit compounds, which are cationic amphiphilic compounds with pK_a values mostly >7.6 and > 9, were shown to induce phospholipidosis in A594-hACE2 cells. This suggests that the limited capacity of these molecules to prevent efficient viral propagation, as compared with Remdesivir, is possibly related to a mode of action that involves phospholipid metabolism.