3 research outputs found
End-to-End Automated Synthesis of C(sp<sup>3</sup>)āEnriched Drug-like Molecules <i>via</i> Negishi Coupling and Novel, Automated LiquidāLiquid Extraction
Herein, we report an end-to-end process including synthesis,
work-up,
purification, and post-purification with minimal human intervention
using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol
are twofold. First, the automated sequential generation of organozinc
reagents from readily available alkyl halides offers a large diversity
of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second,
a fully automated liquidāliquid extraction has been developed
and successfully applied for unattended operations. The workflow was
completed with mass-triggered preparative high-performance liquid
chromatography HPLC, providing an efficient production line of compounds
with enriched sp3 character and better drug-like properties.
The modular nature allows a smooth adaptation to a wide variety of
synthetic methods and protocols and makes it applicable to any medchem
laboratory
Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.
We
report the continuation of a focused medicinal chemistry program aimed
to further optimize a series of imidazoĀ[1,2-<i>a</i>]Āpyrazines
as a novel class of potent and selective phosphodiesterase 10A (PDE10A)
inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic
evaluation allowed the selection of compound <b>25a</b> for
its assessment in preclinical models of psychosis. The evolution of
our medicinal chemistry program, structureāactivity relationship
(SAR) analysis, as well as a detailed pharmacological profile for
optimized lead <b>25a</b> are described
Discovery of <i>N</i>ā(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimerās 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)Āquinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with
modest selectivity versus aggregated Ī²-amyloid (AĪ²). 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