5 research outputs found
Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands: Relationships between Substitution Pattern and σ Receptor Affinity
On the basis of the 6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-<i>c</i>]pyran] framework, a series of more than 30 σ ligands
with versatile substituents in 1-, 2′-, and 6′-position
has been synthesized and pharmacologically evaluated in order to find
novel structure–affinity relationships. It was found that a
cyclohexylmethyl residue at the piperidine <i>N</i>-atom
instead of a benzyl moiety led to increased σ<sub>2</sub> affinity
and therefore to decreased σ<sub>1</sub>/σ<sub>2</sub> selectivity. Small substituents (e.g., OH, OCH<sub>3</sub>, CN,
CH<sub>2</sub>OH) in 6′-position adjacent to the O-atom were
well tolerated by the σ<sub>1</sub> receptor. Removal of the
substituent in 6′-position resulted in very potent but unselective
σ ligands (<b>13</b>). A broad range of substituents with
various lipophilic and <i>H</i>-bond forming properties
was introduced in 2′-position adjacent to the <i>S</i>-atom without loss of σ<sub>1</sub> affinity. However, very
polar and basic substituents in both 2′- and 6′-position
decreased the σ<sub>1</sub> affinity considerably. It is postulated
that the electron density of the thiophene moiety has a big impact
on the σ<sub>1</sub> affinity
Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ<sub>1</sub> Receptor Antagonists: Identification of 4‑{2-[5-Methyl-1-(naphthalen-2-yl)‑1<i>H</i>‑pyrazol-3-yloxy]ethyl}morpholine (S1RA, E‑52862)
The synthesis and pharmacological activity of a new series
of 1-arylpyrazoles as potent σ<sub>1</sub> receptor (σ<sub>1</sub>R) antagonists are reported. The new compounds were evaluated
in vitro in human σ<sub>1</sub>R and guinea pig σ<sub>2</sub> receptor (σ<sub>2</sub>R) binding assays. The nature
of the pyrazole substituents was crucial for activity, and a basic
amine was shown to be necessary, in accordance with known receptor
pharmacophores. A wide variety of amines and spacer lengths between
the amino and pyrazole groups were tolerated, but only the ethylenoxy
spacer and small cyclic amines provided compounds with sufficient
selectivity for σ<sub>1</sub>R vs σ<sub>2</sub>R. The
most selective compounds were further profiled, and compound <b>28</b>, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1<i>H</i>-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high
activity in the mouse capsaicin model of neurogenic pain, emerged
as the most interesting candidate. In addition, compound <b>28</b> exerted dose-dependent antinociceptive effects in several neuropathic
pain models. This, together with its good physicochemical, safety,
and ADME properties, led compound <b>28</b> to be selected as
clinical candidate
Toward β‑Secretase‑1 Inhibitors with Improved Isoform Selectivity
BACE1
is responsible for the first step in APP proteolysis, leading
to toxic Aβ production, and has been indicated to play a key
role in the pathogenesis of Alzheimer’s disease. The related
isoform BACE2 is thought to be involved in processing of the pigment
cell-specific melanocyte protein. To avoid potential effects on pigmentation,
we investigated the feasibility for developing isoform-selective BACE1
inhibitors. Cocrystal structures of 47 compounds were analyzed and
clustered according to their selectivity profiles. Selective BACE1
inhibitors were found to exhibit two distinct conformational features
proximal to the flap and the S3 subpocket. Several new molecules were
designed and tested to make use of this observation. The combination
of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in
lead molecule <b>28</b>, which exhibited ∼50-fold selectivity.
Compared to a nonselective BACE1/2 inhibitor, <b>28</b> showed
significantly less inhibition of PMEL processing in human melanocytes,
indicating good functional selectivity of this inhibitor class
Low estimated glomerular filtration rate is associated with poor outcomes in patients who suffered a large artery atherosclerosis stroke
[[abstract]]Objectives: The relationship between low estimated glomerular filtration rate (eGFR) and the outcome of ischemic stroke remains controversial, despite the close association between kidney dysfunction and atherosclerosis. Methods: This study conducted subgroup analysis using data from the prospective Taiwan Stroke Registry to investigate the relationship between eGFR at the time of admission and 6-month functional outcomes in patients with the large artery atherosclerotic (LAA) subtype of acute ischemic stroke. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and outcomes were defined as modified Rankin Scale and mortality status at 6 months post stroke. Results: Of the 8052 patients with the LAA subtype of acute ischemic stroke in this study, 3312 (41.1%) had eGFR 15 and eGFR <15mL/min/1.73m2, compared with those with NIHSS 0-5 and eGFR 60-119mL/min/1.73m2. Conclusions: Low eGFR was significantly and independently associated with 6-month functional outcomes and mortality in patients with the LAA subtype of acute ischemic stroke. The deleterious relationship between low eGFR levels and mortality following stroke was exacerbated by its synergistic association with stroke severity
Design and Synthesis of β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of β‑Amyloid Peptides
The evaluation of a series of aminoisoindoles as β-site
amyloid
precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery
of a clinical candidate drug for Alzheimer’s disease, (<i>S</i>)-<b>32</b> (AZD3839), are described. The improvement
in permeability properties by the introduction of fluorine adjacent
to the amidine moiety, resulting in in vivo brain reduction of Aβ40,
is discussed. Due to the basic nature of these compounds, they displayed
affinity for the human ether-a-go-go related gene (hERG) ion channel.
Different ways to reduce hERG inhibition and increase hERG margins
for this series are described, culminating in (<i>S</i>)-<b>16</b> and (<i>R</i>)-<b>41</b> showing large
in vitro margins with BACE1 cell IC<sub>50</sub> values of 8.6 and
0.16 nM, respectively, and hERG IC<sub>50</sub> values of 16 and 2.8
μM, respectively. Several compounds were advanced into pharmacodynamic
studies and demonstrated significant reduction of β-amyloid
peptides in mouse brain following oral dosing