3 research outputs found
Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX<sub>3</sub>CR1)
We have developed two parallel series,
A and B, of CX<sub>3</sub>CR1 antagonists for the treatment of multiple
sclerosis. By modifying
the substituents on the 7-amino-5-thio-thiazoloÂ[4,5-<i>d</i>]Âpyrimidine core structure, we were able to achieve compounds with
high selectivity for CX<sub>3</sub>CR1 over the closely related CXCR2
receptor. The structure–activity relationships showed that
a leucinol moiety attached to the core-structure in the 7-position
together with α-methyl branched benzyl derivatives in the 5-position
displayed promising affinity, and selectivity as well as physicochemical
properties, as exemplified by compounds <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective
orally available CX<sub>3</sub>CR1 antagonists
New Aminoimidazoles as β‑Secretase (BACE-1) Inhibitors Showing Amyloid‑β (Aβ) Lowering in Brain
Amino-2<i>H</i>-imidazoles are described as
a new class
of BACE-1 inhibitors for the treatment of Alzheimer’s disease.
Synthetic methods, crystal structures, and structure–activity
relationships for target activity, permeability, and hERG activity
are reported and discussed. Compound (<i>S</i>)-<b>1m</b> was one of the most promising compounds in this report, with high
potency in the cellular assay and a good overall profile. When guinea
pigs were treated with compound (<i>S</i>)-<b>1m</b>, a concentration and time dependent decrease in Aβ40 and Aβ42
levels in plasma, brain, and CSF was observed. The maximum reduction
of brain Aβ was 40–50%, 1.5 h after oral dosing (100
μmol/kg). The results presented highlight the potential of this
new class of BACE-1 inhibitors with good target potency and with low
effect on hERG, in combination with a fair CNS exposure in vivo
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