We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analog, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with an IC50 of 89 nM. However, cytotoxicity remained high, and the ADME data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogs, NBD-14270 (8), showed a marked improvement in cytotoxicity, with a 3-fold and 58-fold improvements in SI values compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.