An organophotoredox-catalyzed
decarboxylative cross-coupling between
azole nucleophiles and aliphatic carboxylic acid-derived redox-active
esters is demonstrated. This protocol efficiently installs various
tertiary or secondary alkyl fragments onto the nitrogen atom of azole
nucleophiles under mild and transition-metal-free conditions. The
pyridinium additive successfully inhibits the formation of elimination
byproducts from the carbocation intermediate. This reaction is applicable
to the synthesis of a protein-degrader-like molecule containing an
azole and a thalidomide.
[reaction: see text] A conjugated pi-electron compound, 2-aryl-3-silyl-1,3-butadiene, was easily prepared from 1-benzyloxy-3-silyl-2-propyne, bis(iodozincio)methane, and an aryl halide in the presence of nickel catalyst. A subsequent cross-coupling reaction of the product with another aryl halide gave an unsymmetrical 2,3-diaryl-1,3-butadiene efficiently.
Inhibition of glucosylceramide
synthase (GCS) is a major therapeutic
strategy for Gaucher’s disease and has been suggested as a
potential target for treating Parkinson’s disease. Herein,
we report the discovery of novel brain-penetrant GCS inhibitors. Assessment
of the structure–activity relationship revealed a unique pharmacophore
in this series. The lipophilic ortho-substituent of aromatic ring
A and the appropriate directionality of aromatic ring B were key for
potency. Optimization of the absorption, distribution, metabolism,
elimination, toxicity (ADMETox) profile resulted in the discovery
of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based
scaffold hopping was performed to mitigate safety concerns associated
with T-036. The ring opening of T-036 resulted
in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent
manner in the plasma and cortex of mice. Finally, we discuss the structural
aspects of the compounds that impart a unique inhibition mode and
lower the cardiovascular risk.
This publication is part of a joint Special Collection with EurJIC on "Main Group Catalysis". Please check the ChemCatChem homepage for more articles in the collection.
To discover a novel
series of potent inhibitors of enteropeptidase,
a membrane-bound serine protease localized to the duodenal brush border,
4-guanidinobenzoate derivatives were evaluated with minimal systemic
exposure. The
1c
docking model enabled the installation
of an additional carboxylic acid moiety to obtain an extra interaction
with enteropeptidase, yielding
2a
. The oral administration
of
2a
significantly elevated the fecal protein output,
a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas
subcutaneous administration did not change this parameter. Thus, systemic
exposure of
2a
was not required for its pharmacological
effects. Further optimization focusing on the in vitro IC
50
value and
T
1/2
, an indicator of dissociation
time, followed by enhanced in vivo pharmacological activity based
on the ester stability of the compounds, revealed two series of potent
enteropeptidase inhibitors, a dihydrobenzofuran analogue (
(
S
)-5b
, SCO-792) and phenylisoxazoline (
6b
), which exhibited potent anti-obesity effects despite their low
systemic exposure following their oral administration to DIO rats.
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