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Novel Competitive, Nonpeptidic, SARS-CoV‑2 Mpro Inhibitors with Improved Solubility
Zafer Sahin1, Mario Rivera1, Yanli Yang1
1Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia 30322, United States.
Abstract:
In continuation of our previous work wherein we described novel, nonpeptidic competitive inhibitors of the SARS-CoV-2 main protease, we here describe our efforts to improve upon these compounds by improving water solubility and metabolic stability. As predicted by FEP+ solubility studies, disrupting the coplanar arrangement of the aromatic rings led to significantly improved compound aqueous solubility, unfortunately with an unacceptable loss in potency. Attempts to improve compound metabolic stability by avoiding aromatic moieties occupying the S4 pocket, while retaining compound potency by modification of the pyridyl ring occupying the S1 pocket, were also investigated.
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