Discovery of γ-secretase modulators with a novel activity profile by text-based virtual screening.
We present an integrated approach to identify and optimize a novel class of γ-secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease. They modulate the γ-secretase product spectrum (i.e., amyloid-β (Aβ) peptides of different length) and induce a shift from toxic Aβ42 to shorter Aβ species such as Aβ38 with no or minimal effect on the overall rate of γ-secretase cleavage. We describe the identification of a series of 4-hydroxypyridin-2-one derivatives, which display a novel type of γ-secretase modulation with equipotent inhibition of Aβ42 and Aβ38 peptide species.
Department of Neuropathology, Heinrich-Heine-University, D-40225 Duesseldorf, Germany.
Heiko
H
Zettl
Julia
J
Ness
Volker
V
Hähnke
Dirk
D
Beher
Thorsten
T
Jumpertz
Arman
A
Saric
Karlheinz
K
Baumann
Claus U
CU
Pietrzik
Bruno
B
Bulic
Gisbert
G
Schneider
Sascha
S
Weggen
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D011728:Pyridones; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D011725:Pyridines; D011728:Pyridones; C534143:4-pyridone; D053829:Amyloid Precursor Protein Secretases