13 research outputs found
Construction of the Azocane (Azacyclooctane) Moiety of the <i>Lycopodium</i> Alkaloid Lycopladine H via an Intramolecular Hydroaminomethylation Strategy
An efficient synthetic strategy has been developed for annulation of an azocane ring onto a bicyclo[2.2.2]octane scaffold via an intramolecular hydroaminomethylation protocol to generate an advanced intermediate bearing three of the four rings of the structurally unique <i>Lycopodium</i> alkaloid lycopladine H (<b>1</b>)
A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis
Discovering compounds and mechanisms
for inhibiting ferroptosis,
a form of regulated, nonapoptotic cell death, has been of great interest
in recent years. In this study, we demonstrate the ability of XJB-5-131,
JP4-039, and other nitroxide-based lipid peroxidation mitigators to
prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells.
Several analogues of the reactive oxygen species (ROS) scavengers
XJB-5-131 and JP4-039 were synthesized to probe structure–activity
relationships and the influence of subcellular localization on the
potency of these novel ferroptosis suppressors. Their biological activity
correlated well over several orders of magnitude with their structure,
relative lipophilicity, and respective enrichment in mitochondria,
revealing a critical role of intramitochondrial lipid peroxidation
in ferroptosis. These results also suggest that preventing mitochondrial
lipid oxidation might offer a viable therapeutic opportunity in ischemia/reperfusion-induced
tissue injury, acute kidney injury, and other pathologies that involve
ferroptotic cell death pathways
An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility
Low
aqueous solubility is a common challenge in drug discovery
and development and can lead to inconclusive biological assay results.
Attaching small, polar groups that do not interfere with the bioactivity
of the pharmacophore often improves solubility, but there is a dearth
of viable neutral moieties available for this purpose. We have modified
several poorly soluble drugs or drug candidates with the oxetanyl
sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases
a moderate to large improvement of aqueous solubility. Furthermore,
the membrane permeability of a test sample was enhanced compared to
the parent compound
Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects
The
mood stabilizer lithium, the first-line treatment for bipolar
disorder, is hypothesized to exert its effects through direct inhibition
of glycogen synthase kinase 3 (GSK3) and indirectly by increasing
GSK3’s inhibitory serine phosphorylation. GSK3 comprises two
highly similar paralogs, GSK3α and GSK3β, which are key
regulatory kinases in the canonical Wnt pathway. GSK3 stands as a
nodal target within this pathway and is an attractive therapeutic
target for multiple indications. Despite being an active field of
research for the past 20 years, many GSK3 inhibitors demonstrate either
poor to moderate selectivity versus the broader human kinome or physicochemical
properties unsuitable for use in <i>in vitro</i> systems
or <i>in vivo</i> models. A nonconventional analysis of
data from a GSK3β inhibitor high-throughput screening campaign,
which excluded known GSK3 inhibitor chemotypes, led to the discovery
of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled
kinome-wide selectivity for the GSK3 kinases. Taking advantage of
an uncommon tridentate interaction with the hinge region of GSK3,
we developed highly selective and potent GSK3 inhibitors, <b>BRD1652</b> and <b>BRD0209</b>, which demonstrated <i>in vivo</i> efficacy in a dopaminergic signaling paradigm modeling mood-related
disorders. These new chemical probes open the way for exclusive analyses
of the function of GSK3 kinases in multiple signaling pathways involved
in many prevalent disorders
Functionally Biased D2R Antagonists: Targeting the β‑Arrestin Pathway to Improve Antipsychotic Treatment
Schizophrenia
is a severe neuropsychiatric disease that lacks completely
effective and safe therapies. As a polygenic disorder, genetic studies
have only started to shed light on its complex etiology. To date,
the positive symptoms of schizophrenia are well-managed by antipsychotic
drugs, which primarily target the dopamine D2 receptor (D2R). However,
these antipsychotics are often accompanied by severe side effects,
including motoric symptoms. At D2R, antipsychotic drugs antagonize
both G-protein dependent (Gα<sub>i/o</sub>) signaling and G-protein
independent (β-arrestin) signaling. However, the relevant contributions
of the distinct D2R signaling pathways to antipsychotic efficacy and
on-target side effects (motoric) are still incompletely understood.
Recent evidence from mouse genetic and pharmacological studies point
to β-arrestin signaling as the major driver of antipsychotic
efficacy and suggest that a β-arrestin biased D2R antagonist
could achieve an additional level of selectivity at D2R, increasing
the therapeutic index of next generation antipsychotics. Here, we
characterize <b>BRD5814</b>, a highly brain penetrant β-arrestin
biased D2R antagonist. <b>BRD5814</b> demonstrated good target
engagement <i>via</i> PET imaging, achieving efficacy in
an amphetamine-induced hyperlocomotion mouse model with strongly reduced
motoric side effects in a rotarod performance test. This proof of
concept study opens the possibility for the development of a new generation
of pathway selective antipsychotics at D2R with reduced side effect
profiles for the treatment of schizophrenia