Continuous Flow α‑Arylation of <i>N</i>,<i>N</i>‑Dialkylhydrazones under Visible-Light Photoredox Catalysis

The first direct α-arylation of aldehyde-derived <i>N</i>,<i>N</i>-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α′-diaryl-<i>N</i>,<i>N</i>-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-<i>N</i>,<i>N</i>-dialkylhydrazones on a multigram scale has also been established

Imidazo[1,2-<i>a</i>]pyridines: Orally Active Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of <b>27o</b>. With good potency and selectivity for the mGlu2 receptor, <b>27o</b> affected sleep–wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity

Discovery of <i>N</i>‑(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified <i>N</i>-(6-methylpyridin-2-yl)­quinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine <b>75</b>, a potent and selective tau aggregate binder with potential as a tau PET tracer