7 research outputs found
Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ–Fibrinogen Interaction and Aβ-Induced Contact System Activation
Accumulating
evidence suggests that fibrinogen, a key protein in
the coagulation cascade, plays an important role in circulatory dysfunction
in Alzheimer’s disease (AD). Previous work has shown that the
interaction between fibrinogen and β-amyloid (Aβ), a hallmark
pathological protein in AD, induces plasmin-resistant abnormal blood
clots, delays fibrinolysis, increases inflammation, and aggravates
cognitive function in mouse models of AD. Since Aβ oligomers
have a much stronger affinity for fibrinogen than Aβ monomers,
we tested whether amyloid aggregation inhibitors could block the Aβ–fibrinogen
interaction and found that some Aβ aggregation inhibitors showed
moderate inhibitory efficacy against this interaction. We then modified
a hit compound so that it not only showed a strong inhibitory efficacy
toward the Aβ–fibrinogen interaction but also retained
its potency toward the Aβ42 aggregation inhibition process.
Furthermore, our best hit compound, TDI-2760, modulated Aβ42-induced
contact system activation, a pathological condition observed in some
AD patients, in addition to inhibiting the Aβ–fibrinogen
interaction and Aβ aggregation. Thus, TDI-2760 has the potential
to lessen vascular abnormalities as well as Aβ aggregation-driven
pathology in AD
Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies
Macrocyclic Hedgehog (Hh) pathway inhibitors have been
discovered
with improved potency and maximal inhibition relative to the previously
reported macrocycle robotnikinin. Analogues were prepared using a
modular and efficient build-couple-pair (BCP) approach, with a ring-closing
metathesis step to form the macrocyclic ring. Varying the position
of the macrocycle nitrogen and oxygen atoms provided inhibitors with
improved activity in cellular assays; the most potent analogue was <b>29</b> (BRD-6851), with an IC<sub>50</sub> of 0.4 μM against
C3H10T1/2 cells undergoing Hh-induced activation, as measured by <i>Gli1</i> transcription and alkaline phosphatase induction. Studies
with Patched knockout (<i>Ptch</i><sup>–/–</sup>) cells and competition studies with the Smoothened (Smo) agonists
SAG and purmorphamine demonstrate that in contrast to robotnikinin,
select analogues are Smo antagonists
Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile
In 2013, the Centers
for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part
due to the emergence of highly virulent fluoroquinolone-resistant
strains. Limited therapeutic options currently exist, many of which
result in disease relapse. We sought to identify molecules specifically
targeting <i>C. difficile</i> in high-throughput screens
of our diversity-oriented synthesis compound collection. We identified
two scaffolds with apparently novel mechanisms of action that selectively
target <i>C. difficile</i> while having little to no
activity against other intestinal anaerobes; preliminary evidence
suggests that compounds from one of these scaffolds target the glutamate
racemase. In vivo efficacy data suggest that both compound series
may provide lead optimization candidates
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926
The
formation of the d-homocyclopamine ring system in
IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective
cyclopropanation followed by a stereoselective acid-catalyzed carbocation
rearrangement. In order to perform large-scale cyclopropanation reactions,
we developed new iodomethylzinc bis(aryl)phosphate reagents that were
found to be both effective and safe. These soluble reagents can be
prepared under mild conditions and are stable during the course of
the reaction. Importantly, they have favorable energetics relative
to other cyclopropanating agents such as EtZnCH<sub>2</sub>I. Herein,
we describe the process optimization studies that led to successful
large-scale production of the d-homocyclopamine core necessary
for IPI-926