Majority of current circulating influenza A viruses carry the S31N mutation in their M2 genes, rendering AM2-S31N as a high profile antiviral drug target. With our continuous interest in developing AM2-S31N channel blockers as novel antivirals targeting both oseltamivir-sensitive and -resistant influenza A viruses, we report herein the structure–property relationship studies of AM2-S31N inhibitors. The goal was to identify lead compounds with improved microsomal stability and membrane permeability. Two lead compounds, 10d and 10e, were found to have high mouse and human liver microsomal stability (T1/2 > 145 min) and membrane permeability (>200 nm/s). Both compounds also inhibit both currently circulating oseltamivir-sensitive and -resistant human influenza A viruses (H1N1 and H3N2) with EC50 values ranging from 0.4 to 2.8 μM and a selectivity index of >100. We also showed for the first time that AM2-S31N channel blockers such as 10e inhibited influenza virus replication at both low and high multiply of infection (102–106 pfu/mL) and the inhibition was not cell-type dependent. Overall, these studies have identified two promising lead candidates for further development as antiviral drugs against drug-resistant influenza A viruses.