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_1′, S₁, and S₂ 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 (mGlu₅) 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 (mGlu₅) 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 mGlu₅ 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 mGlu₅ 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 mGlu₅ PAMs

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu₅) 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 mGlu₅ 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 mGlu₅ as well as antagonist activity at mGlu₃. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered <b>12c</b> (VU0405372), a selective mGlu₅ PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis