5 research outputs found
Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors
The synthesis of 4ā²,6ā²-dihydrospiroĀ[piperidine-4,5ā²-pyrazoloĀ[3,4-<i>c</i>]Āpyridin]-7ā²(2ā²<i>H</i>)-one-based
acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown
N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized
from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a
streamlined 10-step synthesis requiring only one chromatography procedure.
The described synthetic strategy provides pyrazolo-fused spirolactams
from halogenated benzylic arenes and cyclic carboxylates. Key steps
include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both
conventional and flow conditions to install the hindered amine via
a stable and isolable isocyanate. Finally, a Parham-type cyclization
was used to furnish the desired spirolactam. An analogous route provided
efficient access to the related N-1 isopropyl lactam series. Elaboration
of the lactam cores via amidation enabled synthesis of novel ACC inhibitors
and the identification of potent analogues
Glycomimetic Ligands for the Human Asialoglycoprotein Receptor
The asialoglycoprotein receptor (ASGPR) is a high-capacity
galactose-binding
receptor expressed on hepatocytes that binds its native substrates
with low affinity. More potent ligands are of interest for hepatic
delivery of therapeutic agents. We report several classes of galactosyl
analogues with varied substitution at the anomeric, C2-, C5-, and
C6-positions. Significant increases in binding affinity were noted
for several trifluoromethylacetamide derivatives without covalent
attachment to the protein. A variety of new ligands were obtained
with affinity for ASGPR as good as or better than that of the parent <i>N</i>-acetylgalactosamine, showing that modification
on either side of the key C3,C4-diol moiety is well tolerated, consistent
with previous models of a shallow binding pocket. The galactosyl pyranose
motif therefore offers many opportunities for the attachment of other
functional units or payloads while retaining low-micromolar or better
affinity for the ASGPR
Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure
Acetyl-CoA carboxylase (ACC) catalyzes
the rate-determining step
in <i>de novo</i> lipogenesis and plays a crucial role in
the regulation of fatty acid oxidation. Alterations in lipid metabolism
are believed to contribute to insulin resistance; thus inhibition
of ACC offers a promising option for intervention in type 2 diabetes
mellitus. Herein we disclose a series of ACC inhibitors based on a
spirocyclic pyrazololactam core. The lactam series has improved chemical
and metabolic stability relative to our previously reported pyrazoloketone
series, while retaining potent inhibition of ACC1 and ACC2. Optimization
of the pyrazole and amide substituents led to quinoline amide <b>21</b>, which was advanced to preclinical development
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor
A compact and stable bicyclic bridged
ketal was developed as a
ligand for the asialoglycoprotein receptor (ASGPR). This compound
showed excellent ligand efficiency, and the molecular details of binding
were revealed by the first X-ray crystal structures of ligand-bound
ASGPR. This analogue was used to make potent di- and trivalent binders
of ASGPR. Extensive characterization of the function of these compounds
showed rapid ASGPR-dependent cellular uptake in vitro and high levels
of liver/plasma selectivity in vivo. Assessment of the biodistribution
in rodents of a prototypical Alexa647-labeled trivalent conjugate
showed selective hepatocyte targeting with no detectable distribution
in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed
hepatocellular uptake and prolonged retention compared to a similar
GalNAc derived trimer conjugate. Selective release in the liver of
a passively permeable small-molecule cargo was achieved by retro-DielsāAlder
cleavage of an oxanorbornadiene linkage, presumably upon encountering
intracellular thiol. Therefore, the multicomponent construct described
here represents a highly efficient delivery vehicle to hepatocytes
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor
A compact and stable bicyclic bridged
ketal was developed as a
ligand for the asialoglycoprotein receptor (ASGPR). This compound
showed excellent ligand efficiency, and the molecular details of binding
were revealed by the first X-ray crystal structures of ligand-bound
ASGPR. This analogue was used to make potent di- and trivalent binders
of ASGPR. Extensive characterization of the function of these compounds
showed rapid ASGPR-dependent cellular uptake in vitro and high levels
of liver/plasma selectivity in vivo. Assessment of the biodistribution
in rodents of a prototypical Alexa647-labeled trivalent conjugate
showed selective hepatocyte targeting with no detectable distribution
in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed
hepatocellular uptake and prolonged retention compared to a similar
GalNAc derived trimer conjugate. Selective release in the liver of
a passively permeable small-molecule cargo was achieved by retro-DielsāAlder
cleavage of an oxanorbornadiene linkage, presumably upon encountering
intracellular thiol. Therefore, the multicomponent construct described
here represents a highly efficient delivery vehicle to hepatocytes