2 research outputs found
Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3β (GSK3β) Inhibitors for Alzheimer’s Disease: Design, Synthesis, and Characterization of Pyrazines
Glycogen synthase kinase-3β, also called tau phosphorylating
kinase, is a proline-directed serine/threonine kinase which was originally
identified due to its role in glycogen metabolism. Active forms of
GSK3β localize to pretangle pathology including dystrophic neuritis
and neurofibrillary tangles in Alzheimer’s disease (AD) brain.
By using a high throughput screening (HTS) approach to search for
new chemical series and cocrystallization of key analogues to guide
the optimization and synthesis of our pyrazine series, we have developed
highly potent and selective inhibitors showing cellular efficacy and
blood–brain barrier penetrance. The inhibitors are suitable
for in vivo efficacy testing and may serve as a new treatment strategy
for Alzheimer’s disease
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