Preclinical optimization of gp120 entry-antagonists as anti-HIV-1 agents with improved cytotoxicity and ADME properties through rational design, synthesis, and antiviral evaluation.

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ID: 92783
2020
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Abstract
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.
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curreli2020preclinicaljournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Curreli, Francesca;Ahmed, Shahad;Benedict Victor, Sofia Mary;Iusupov, Ildar;Markov, Pavel;Kurkin, Alexander V;Altieri, Andrea;Debnath, Asim Kumar;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b02149
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