Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity
Journal of Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 11, 2025
NLRP3
is
a
danger
sensor
protein
responsible
for
inflammasome
activation.
This
leads
to
pro-inflammatory
cytokines
release,
like
IL-1β,
and
pyroptosis,
regulated
cell
death.
Mounting
evidence
associates
excessive
activation
neurodegenerative
conditions,
such
as
Alzheimer's
Parkinson's
diseases.
Thus,
inhibitors
could
potentially
provide
therapeutic
benefit
these
disorders.
We
describe
here
the
evolution
of
relying
on
pyridazine-based
motif
their
key
interactions
with
NLRP3.
A
Cryo-EM
structure
helped
optimizing
protein-ligand
complementarity.
Subsequently,
conformational
NMR
studies
pointed
efforts
toward
5,6-bicyclic
cores
that
allowed
balance
between
brain
penetration
undesirable
properties,
hERG
inhibition.
The
effort
culminated
in
compound
19,
which
showed
moderate
(mouse)
good
(rat)
was
active
at
low
dose
an
LPS
challenge
model.
Importantly,
earlier
central
neuroinflammation
model
providing
valuable
proof
concept
Language: Английский
Understanding a Potential Role for the NLRP3 Inflammasome in Placenta‐Mediated Pregnancy Complications
American Journal of Reproductive Immunology,
Journal Year:
2025,
Volume and Issue:
93(4)
Published: April 1, 2025
ABSTRACT
Stillbirth
affects
approximately
2
million
pregnancies
annually
and
is
closely
linked
to
placental
dysfunction,
which
may
also
present
clinically
as
foetal
growth
restriction
(FGR)
or
pre‐eclampsia
(PE).
Placental
dysfunction
can
arise
from
a
range
of
insults,
including
the
inflammatory
conditions
villitis
unknown
aetiology
(VUE)
chronic
histiocytic
intervillositis
(CHI).
Despite
ample
research
regarding
pathophysiology
literature
surrounding
inflammation
more
limited,
with
no
currently
established
treatments.
In
absence
infection,
hypothesised
be
stimulated
by
damage‐associated
molecular
patterns
(DAMPs),
known
sterile
inflammation.
The
NLRP3
inflammasome,
protein
scaffold
that
unites
within
cytosol
cells,
proposed
contributor.
inflammasome
dysregulated
in
numerous
diseases
has
shown
evidence
activation
through
pathway
via
DAMPs.
Studies
have
demonstrated
upregulation
its
components
placentally‐mediated
pregnancy
pathologies.
However,
link
between
seen
these
disorders
not
yet
firmly
established.
This
manuscript
aims
review
discuss
association
identify
potential
therapeutic
interventions
for
this
pathological
response.
Language: Английский
[18F]NP3‐627, a candidate PET imaging agent targeting the NLRP3 inflammasome in the central nervous system
ChemMedChem,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 14, 2024
We
describe
the
identification
of
a
candidate
positron
emission
tomography
(PET)
imaging
agent
for
NLRP3
protein.
plays
critical
role
in
immune
system
and
has
proven
difficult
target
development
agents
due
to
its
low
cell-specific
expression
profile.
A
recently
described
series
pyridazine-based
inhibitors,
with
improved
permeability
brain-penetration
properties,
was
used
as
starting
point
suitable
PET
agent.
Optimization
affinity,
non-specific
binding
pharmacokinetic
properties
led
aminopyridazine
(R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)pyridazin-3-yl)-5-fluoro-3-methylphenol
(17
b),
which
meets
preclinical
profile
successful
agent,
whose
tritiated
version
demonstrated
excellent
specificity
radioligand
saturation
assay,
confirming
potential.
Language: Английский
Brain Penetrant NLRP3 Inhibitors: The Discovery of a Panacea?
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 2, 2024
The
NLRP3
inflammasome
has
attracted
much
interest
as
a
drug
target;
however,
many
of
the
first
wave
inhibitors
were
derived
from
single
aryl
sulfonylurea
starting
point.
physicochemical
properties
this
molecule
and
most
derivatives
are
not
amenable
to
high
brain
penetration,
thus
limiting
their
potential
effectiveness
against
disease
targets
where
is
required.
disclosure
novel
pyridazine
phenol
scaffold
facilitated
second
research
toward
brain-penetrant
molecules,
which
may
enable
discovery
treatments
for
Alzheimer's
disease,
Parkinson's
multiple
sclerosis
cardiometabolic
diseases.
Language: Английский