Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy
نویسندگان
چکیده
منابع مشابه
Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
γ-Secretase generates the peptides of Alzheimer's disease, Aβ(40) and Aβ(42), by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, ...
متن کاملγ-Secretase Modulators: Can We Combine Potency with Safety?
γ-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer's approach. γ-Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating γ-secretase may avoid some of the adverse effects observed...
متن کاملTarget of γ-secretase modulators, presenilin marks the spot.
c-Secretase modulators, or GSMs, which reduce the production of Ab42, have emerged as a promising class of compounds for the treatment of Alzheimer’s disease (AD). The target and mechanism of action of GSMs have been controversial as of late, with some evidence suggesting that GSMs function by binding the substrate, amyloid precursor protein (APP), and others claiming action through direct modu...
متن کاملComplex Relationships between Substrate Sequence and Sensitivity to Alterations in γ-Secretase Processivity Induced by γ-Secretase Modulators
γ-Secretase catalyzes the final cleavage of the amyloid precursor protein (APP), resulting in the production of amyloid-β (Aβ) peptides with different carboxyl termini. Presenilin (PSEN) and amyloid precursor protein (APP) mutations linked to early onset familial Alzheimer's disease modify the profile of Aβ isoforms generated, by altering both the initial γ-secretase cleavage site and subsequen...
متن کاملPhenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1.
Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: MedChemComm
سال: 2017
ISSN: 2040-2503,2040-2511
DOI: 10.1039/c6md00406g