3 research outputs found
Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors
In the present paper, we described
the design, synthesis, SAR,
and biological profile of a novel spirocyclic sulfone series of γ-secretase
inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic
ring system to stabilize the active chair conformation of the parent
γ-secretase inhibitors. The resulting series is devoid of the
CYP2C9 inhibition liability of MRK-560. A few representative analogs
were assessed in a nontransgenic animal model of Alzheimer’s
disease (AD), demonstrating reduction of amyloid-β (Aβ)
in the CNS after acute oral dosing. A spirocyclic phosphonate was
identified as the optimal ring system for both potency and pharmacokinetics.
Compared to GSIs studied in the clinic, representative spirocyclic
phosphonate <b>18a(−)</b> features improved selectivity
for the inhibition of the PS-1 isoform of γ-secretase (33-fold
vs PS-2), which may alleviate the adverse effect profile of the clinical
GSIs
Magnetization and spin gap in two-dimensional organic ferrimagnet BIPNNBNO
A magnetization process in the two-dimensional ferrimagnet BIPNNBNO is analyzed. The compound consists of ferrimagnetic (1,1/2) chains coupled by two sorts of antiferromagnetic interaction. Whereas the behavior of the magnetization curve in higher magnetic fields can be understood within a process for the separate ferrimagnetic chain, the appearance of the singlet plateau at lower fields is an example of non-Lieb-Mattis type ferrimagnetism. By using the exact diagonalization technique for finite clusters of size 4×6, 4×8 and 4×10 we show that the interchain frustration coupling plays an essential role in stabilization of the singlet phase. These results are complemented by an analysis of four cylindrically coupled ferrimagnetic (1,1/2) chains via an Abelian bosonization technique and an effective theory based on the XXZ spin-1/2 Heisenberg model when the interchain interactions are sufficiently weak/strong, respectively. © 2012 IOP Publishing Ltd
Synthesis and SAR Studies of Fused Oxadiazines as γ‑Secretase Modulators for Treatment of Alzheimer's Disease
Fused oxadiazines (<b>3</b>) were discovered as
selective and orally bioavailable γ-secretase modulators (GSMs)
based on the structural framework of oxadiazoline GSMs. Although structurally
related, initial modifications showed that structure–activity
relationships (SARs) did not translate from the oxadiazoline to the
oxadiazine series. Subsequent SAR studies on modifications at the
C3 and C4 positions of the fused oxadiazine core helped to identify
GSMs such as compounds <b>8r</b> and <b>8s</b> that were
highly efficacious in vitro and in vivo in a number of animal models
with highly desirable physical and pharmacological properties. Further
improvements of in vitro activity and selectivity were achieved by
the preparation of fused morpholine oxadiazines. The shift in specificity
of APP cleavage rather than a reduction in overall γ-secretase
activity and the lack of changes in substrate accumulation and Notch
processing as observed in the animal studies of compound <b>8s</b> confirm that the oxadiazine series of compounds are potent GSMs