jm9b02149_si_002.csv (3.79 kB)
Preclinical Optimization of gp120 Entry Antagonists as anti-HIV‑1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation
dataset
posted on 2020-02-14, 22:29 authored by Francesca Curreli, Shahad Ahmed, Sofia M. Benedict Victor, Ildar R. Iusupov, Dmitry S. Belov, Pavel O. Markov, Alexander V. Kurkin, Andrea Altieri, Asim K. DebnathWe
previously reported a milestone in the optimization of NBD-11021,
an HIV-1 gp120 antagonist, by developing a new and novel analogue,
NBD-14189 (Ref1), which showed antiviral activity against
HIV-1HXB2, with a half maximal inhibitory concentration
of 89 nM. However, cytotoxicity remained high, and the absorption,
distribution, metabolism, and excretion (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 analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold
and 58-fold improvements in selectivity index value 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.