2 research outputs found
Design and Synthesis of P1–P3 Macrocyclic Tertiary-Alcohol-Comprising HIV‑1 Protease Inhibitors
To
study P1–P3 macrocyclizations of previously reported
tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three
new 14- and 15-member macrocyclic PIs were designed, synthesized by
ring-closing metathesis, and evaluated alongside with 10 novel linear
PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1
protease are presented, analyzed, and discussed. The macrocyclic structures
exhibited higher activities than the linear precursors with <i>K</i><sub>i</sub> and EC<sub>50</sub> values down to 3.1 nM
and 0.37 μM, respectively
Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
The limited efficacy, in particular
against the genotype 1 virus,
as well as the variety of side effects associated with the current
therapy for hepatitis C virus (HCV) infection necessitates more efficacious
drugs. We found that phosphoramidate prodrugs of 2′-deoxy-2′-spirooxetane
ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase
inhibitors, displaying EC<sub>50</sub> values ranging from 0.2 to
>98 μM, measured in the Huh7-replicon cell line, with no
apparent
cytotoxicity (CC<sub>50</sub> > 98.4 μM). Confirming recent
findings, the 2′-spirooxetane moiety was identified as a novel
structural motif in the field of anti-HCV nucleosides. A convenient
synthesis was developed that enabled the synthesis of a broad set
of nucleotide prodrugs with varying substitution patterns. Extensive
formation of the triphosphate metabolite was observed in both rat
and human hepatocyte cultures. In addition, after oral dosing of several
phosphoramidate derivatives of compound <b>21</b> to rats, substantial
hepatic levels of the active triphosphate metabolite were found