title: First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.
abstract: γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.
authors.affiliation: Department of Neuroscience, AstraZeneca, CNS/PAIN iMED, S-151 85 Södertälje, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Borgegard
authors.forename: Anders
authors.initials: A
authors.lastname: Juréus
authors.forename: Fredrik
authors.initials: F
authors.lastname: Olsson
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosqvist
authors.forename: Alan
authors.initials: A
authors.lastname: Sabirsh
authors.forename: Didier
authors.initials: D
authors.lastname: Rotticci
authors.forename: Kim
authors.initials: K
authors.lastname: Paulsen
authors.forename: Rebecka
authors.initials: R
authors.lastname: Klintenberg
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yan
authors.forename: Magnus
authors.initials: M
authors.lastname: Waldman
authors.forename: Kia
authors.initials: K
authors.lastname: Stromberg
authors.forename: Johan
authors.initials: J
authors.lastname: Nord
authors.forename: Jonas
authors.initials: J
authors.lastname: Johansson
authors.forename: Anna
authors.initials: A
authors.lastname: Regner
authors.forename: Santiago
authors.initials: S
authors.lastname: Parpal
authors.forename: David
authors.initials: D
authors.lastname: Malinowsky
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Radesater
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Li
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Singh
authors.forename: Hakan
authors.initials: H
authors.lastname: Eriksson
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002474:Cell-Free System; D003984:Dibenzazepines / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D036122:Receptor, EphA4 / Q000378:metabolism; D036183:Receptor, EphB2 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C555019:1-(1-(4-fluorophenyl)ethyl)-3-((3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)methylene)-2-piperidinone; C572500:AZ1136; C572501:AZ3303; C572499:AZ4800; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; D002219:Carbamates; D003984:Dibenzazepines; D004151:Dipeptides; D007093:Imidazoles; C410009:L 685458; C510791:MRK 560; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D010880:Piperidines; D011714:Pyrans; D011725:Pyridines; D011743:Pyrimidines; D051880:Receptors, Notch; D013449:Sulfonamides; D013467:Sulindac; D005480:Flurbiprofen; C025462:sulindac sulfide; D036122:Receptor, EphA4; D036183:Receptor, EphB2; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine; D000409:Alanine