4 research outputs found
Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus
Toll-like receptor (TLR) 7 and 8
agonists can potentially be used
in the treatment of viral infections and are particularly promising
for chronic hepatitis B virus (HBV) infection. An internal screening
effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist.
This provided a novel alternative over the previously reported adenine
and pteridone type of agonists. Structure–activity relationship,
lead optimization, in silico docking, pharmacokinetics, and demonstration
of ex vivo and in vivo cytokine production of the lead compound are
presented
2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus
A novel
series of 2,4-diaminoquinazolines was identified as potent
dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target
activity. The stereochemistry of the amino alcohol was found to influence
the TLR7/8 selectivity with the (<i>R</i>) isomer resulting
in selective TLR8 agonism. Lead optimization toward a dual agonist
afforded (<i>S</i>)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol <b>31</b> as a potent analog, being structurally different from previously
described dual agonists (McGowan J. Med. Chem. 2016, 59, 7936). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the
desired high first pass profile aimed at limiting systemic cytokine
activation. In vivo pharmacodynamic studies
with lead compound <b>31</b> demonstrated production of cytokines
consistent with TLR7/8 activation in mice and cynomolgus monkeys and
ex vivo inhibition of hepatitis B virus (HBV)
2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus
A novel
series of 2,4-diaminoquinazolines was identified as potent
dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target
activity. The stereochemistry of the amino alcohol was found to influence
the TLR7/8 selectivity with the (<i>R</i>) isomer resulting
in selective TLR8 agonism. Lead optimization toward a dual agonist
afforded (<i>S</i>)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol <b>31</b> as a potent analog, being structurally different from previously
described dual agonists (McGowan J. Med. Chem. 2016, 59, 7936). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the
desired high first pass profile aimed at limiting systemic cytokine
activation. In vivo pharmacodynamic studies
with lead compound <b>31</b> demonstrated production of cytokines
consistent with TLR7/8 activation in mice and cynomolgus monkeys and
ex vivo inhibition of hepatitis B virus (HBV)
Identification and Optimization of Pyrrolo[3,2‑<i>d</i>]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B
Pyrrolo[3,2-<i>d</i>]pyrimidines
were identified as a
new series of potent and selective TLR7 agonists. Compounds were optimized
for their activity and selectivity over TLR8. This presents an advantage
over recently described scaffolds that have residual TLR8 activity,
which may be detrimental to the tolerability of the candidate drug.
Oral administration of the lead compound <b>54</b> effectively
induced a transient interferon stimulated gene (ISG) response in mice
and cynomolgus monkeys. We aimed for a high first pass effect, limiting
cytokine induction systemically, and demonstrated the potential for
the immunotherapy of viral hepatitis