10 research outputs found
Discovery of 1â((2<i>R</i>,4a<i>R</i>,6<i>R</i>,7<i>R</i>,7a<i>R</i>)â2-Isopropoxy-2-oxidodihydroâ4<i>H</i>,6<i>H</i>âspiro[furo[3,2â<i>d</i>][1,3,2]dioxaphosphinine-7,2â˛-oxetan]-6-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)âdione (JNJ-54257099), a 3â˛-5â˛-Cyclic Phosphate Ester Prodrug of 2â˛-Deoxy-2â˛-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition
JNJ-54257099 (<b>9</b>) is
a novel cyclic phosphate ester
derivative that belongs to the class of 2â˛-deoxy-2â˛-spirooxetane
uridine nucleotide prodrugs which are known as inhibitors of the HCV
NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype
(GT) 1b replicon-containing cell line <b>9</b> is devoid of
any anti-HCV activity, an observation attributable to inefficient
prodrug metabolism which was found to be CYP3A4-dependent. In contrast,
in vitro incubation of <b>9</b> in primary human hepatocytes
as well as pharmacokinetic evaluation thereof in different preclinical
species reveals the formation of substantial levels of 2â˛-deoxy-2â˛-spirooxetane
uridine triphosphate (<b>8</b>), a potent inhibitor of the HCV
NS5B polymerase. Overall, it was found that <b>9</b> displays
a superior profile compared to its phosphoramidate prodrug analogues
(e.g., <b>4</b>) described previously. Of particular interest
is the in vivo dose dependent reduction of HCV RNA observed in HCV
infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days
of oral administration of <b>9</b>
Synthesis and Evaluation of <i>N</i>âPhenyl-3-sulfamoyl-benzamide Derivatives as Capsid Assembly Modulators Inhibiting Hepatitis B Virus (HBV)
Small
molecule induced hepatitis B virus (HBV) capsid assembly
modulation is considered an attractive approach for new antiviral
therapies against HBV. Here we describe efforts toward the discovery
of a HBV capsid assembly modulator in a hit-to-lead optimization,
resulting in JNJ-632, a tool compound used to further profile the
mode of action. Administration of JNJ-632 (<b>54</b>) in HBV
genotype D infected chimeric mice resulted in a 2.77 log reduction
of the HBV DNA viral load
Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor
Dengue
is a global public health threat, with about half of the
worldâs population at risk of contracting this mosquito-borne
viral disease. Climate change, urbanization, and global travel accelerate
the spread of dengue virus (DENV) to new areas, including southern
parts of Europe and the US. Currently, no dengue-specific small-molecule
antiviral for prophylaxis or treatment is available. Here, we report
the discovery of JNJ-1802 as a potent, pan-serotype DENV
inhibitor (EC50âs ranging from 0.057 to 11 nM against
the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in
human hepatocytes, the absence of major in vitro pharmacology safety
alerts, and a dose-proportional increase in efficacy against DENV-2
infection in mice were all supportive of its selection as a development
candidate against dengue. JNJ-1802 is being progressed
in clinical studies for the prevention or treatment of dengue
Nucleotide Prodrugs of 2â˛-Deoxy-2â˛-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 2â˛-deoxy-2â˛-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 ÎźM, measured in the Huh7-replicon cell line, with no
apparent
cytotoxicity (CC<sub>50</sub> > 98.4 ÎźM). Confirming recent
findings, the 2â˛-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
Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor
Dengue
is a global public health threat, with about half of the
worldâs population at risk of contracting this mosquito-borne
viral disease. Climate change, urbanization, and global travel accelerate
the spread of dengue virus (DENV) to new areas, including southern
parts of Europe and the US. Currently, no dengue-specific small-molecule
antiviral for prophylaxis or treatment is available. Here, we report
the discovery of JNJ-1802 as a potent, pan-serotype DENV
inhibitor (EC50âs ranging from 0.057 to 11 nM against
the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in
human hepatocytes, the absence of major in vitro pharmacology safety
alerts, and a dose-proportional increase in efficacy against DENV-2
infection in mice were all supportive of its selection as a development
candidate against dengue. JNJ-1802 is being progressed
in clinical studies for the prevention or treatment of dengue
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. Structureâactivity 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)Âamino)Âhexanol <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)
Discovery and Early Development of TMC647055, a Non-Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase
Structure-based macrocyclization
of a 6-carboxylic acid indole
chemotype has yielded potent and selective finger-loop inhibitors
of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization
in conjunction with in vivo evaluation in rats identified several
compounds showing (i) nanomolar potency in HCV replicon cells, (ii)
limited toxicity and off-target activities, and (iii) encouraging
preclinical pharmacokinetic profiles characterized by high liver distribution.
This effort culminated in the identification of TMC647055 (<b>10a</b>), a nonzwitterionic 17-membered-ring macrocycle characterized by
high affinity, long polymerase residence time, and broad genotypic
coverage. In vitro results of the combination of <b>10a</b> with
the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation
of this combination in patients with regard to virus suppression and
resistance emergence. In a phase 1b trial with HCV genotype 1-infected
patients, <b>10a</b> was considered to be safe and well-tolerated
and demonstrated potent antiviral activity, which was further enhanced
in a combination study with TMC435
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)Âamino)Âhexanol <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[3,2â<i>d</i>]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B
PyrroloÂ[3,2-<i>d</i>]Âpyrimidines
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