4 research outputs found
Highly Stereoselective Synthesis of Terminal Chloro-Substituted Propargylamines and Further Functionalization
The
highly stereoselective addition of lithiated chloroacetylene,
derived <i>in situ</i> from <i>cis</i>-1,2-dichloroethene
and methyl lithium, to Ellman chiral <i>N</i>-<i>tert</i>-butanesulfinyl imines is reported. The reaction proceeds in high
yield (up to 98%) and with excellent diastereoselectivity (up to >20:1)
for a variety of aryl, heteroaromatic, alkyl, and α,β-unsaturated
imine substrates. Transformations of the terminal chloro-substituted
propargylamine products are described in which lithium–halogen
exchange yields nucleophilic acetylides that can be quenched to yield
terminal alkynes or intercepted by carbon electrophiles
Discovery, Synthesis, And Structure-Based Optimization of a Series of <i>N</i>‑(<i>tert</i>-Butyl)-2‑(<i>N</i>‑arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease
A high-throughput screen of the NIH molecular libraries
sample
collection and subsequent optimization of a lead dipeptide-like series
of severe acute respiratory syndrome (SARS) main protease (3CLpro)
inhibitors led to the identification of probe compound ML188 (<b>16-(<i>R</i>)</b>, (<i>R</i>)-<i>N</i>-(4-(<i>tert</i>-butyl)phenyl)-<i>N</i>-(2-(<i>tert</i>-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide,
Pubchem CID: 46897844). Unlike the majority of reported coronavirus
3CLpro inhibitors that act via covalent modification of the enzyme, <b>16-(<i>R</i>)</b> is a noncovalent SARS-CoV 3CLpro inhibitor
with moderate MW and good enzyme and antiviral inhibitory activity.
A multicomponent Ugi reaction was utilized to rapidly explore structure–activity
relationships within S<sub>1′</sub>, S<sub>1</sub>, and S<sub>2</sub> enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro
bound with <b>16-(<i>R</i>)</b> was instrumental in
guiding subsequent rounds of chemistry optimization. <b>16-(<i>R</i>)</b> provides an excellent starting point for the further
design and refinement of 3CLpro inhibitors that act by a noncovalent
mechanism of action
Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu<sub>5</sub>) Positive Allosteric Modulators (PAMs): Discovery of 5‑((3-Fluorophenyl)ethynyl)‑<i>N</i>‑(3-methyloxetan-3-yl)picolinamide (ML254)
Positive
allosteric modulators (PAMs) of metabotropic glutamate
receptor 5 (mGlu<sub>5</sub>) represent a promising therapeutic strategy
for the treatment of schizophrenia. Both allosteric agonism and high
glutamate fold-shift have been implicated in the neurotoxic profile
of some mGlu<sub>5</sub> PAMs; however, these hypotheses remain to
be adequately addressed. To develop tool compounds to probe these
hypotheses, the structure–activity relationship of allosteric
agonism was examined within an acetylenic series of mGlu<sub>5</sub> PAMs exhibiting allosteric agonism in addition to positive allosteric
modulation (ago-PAMs). PAM <b>38t</b>, a low glutamate fold-shift
allosteric ligand (maximum fold-shift ∼3.0), was selected as
a potent PAM with no agonism in the in vitro system used for compound
characterization and in two native electrophysiological systems using
rat hippocampal slices. PAM <b>38t</b> (ML254) will be useful
to probe the relative contribution of cooperativity and allosteric
agonism to the adverse effect liability and neurotoxicity associated
with this class of mGlu<sub>5</sub> PAMs
Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu<sub>5</sub>)
Positive
allosteric modulators (PAMs) of metabotropic glutamate
receptor 5 (mGlu<sub>5</sub>) represent a promising therapeutic strategy
for the treatment of schizophrenia. Starting from an acetylene-based
lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone
was identified. We describe further refinements leading to both dihydronaphthyridinone
and tetrahydronaphthyridine mGlu<sub>5</sub> PAMs containing an alkoxy-based
linkage as an acetylene replacement. Exploration of several structural
features including western pyridine ring isomers, positional amides,
linker connectivity/position, and combinations thereof, reveal that
these bicyclic modulators generally exhibit steep SAR and within specific
subseries display a propensity for pharmacological mode switching
at mGlu<sub>5</sub> as well as antagonist activity at mGlu<sub>3</sub>. Structure–activity relationships within a dihydronaphthyridinone
subseries uncovered <b>12c</b> (VU0405372), a selective mGlu<sub>5</sub> PAM with good in vitro potency, low glutamate fold-shift,
acceptable DMPK properties, and in vivo efficacy in an amphetamine-based
model of psychosis