title: The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse.
abstract: There is a substantial body of evidence indicating that beta-amyloid peptides (Abeta) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of Abeta through inhibition of the gamma-secretase enzyme, which cleaves Abeta from the amyloid precursor protein (APP). We demonstrate here that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) attenuates the appearance of amyloid plaques in the Tg2576 mouse. These reductions in plaques were also accompanied by a decrease in the level of reactive gliosis. The morphometric and histological measures agreed with biochemical analysis of Abeta(40) and Abeta(42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing Abeta levels does not significantly alter deposit growth once initiated. Furthermore, we demonstrate that these beneficial effects can be achieved without causing histopathological changes in the ileum, spleen, or thymus as a consequence of blockade of the processing of alternative substrates, such as the Notch family of receptors. This indicates that in vivo a therapeutic window between these substrates seems possible--a key concern in the development of this approach to AD. An understanding of the mechanisms whereby MRK-560 shows differentiation between the APP and Notch proteolytic pathway of gamma-secretase should provide the basis for the next generation of gamma-secretase inhibitors.
authors.affiliation: Department of In Vivo Neuroscience, Merck Sharp And Dohme, Neurosciene Research Centre, Harlow, UK. jonathan.best@daniolabs.com
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Best
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.forename: Michael A
authors.initials: MA
authors.lastname: Reilly
authors.forename: Ruth
authors.initials: R
authors.lastname: O'Donnell
authors.forename: Huw D
authors.initials: HD
authors.lastname: Lewis
authors.forename: Semantha
authors.initials: S
authors.lastname: Ellis
authors.forename: Neil
authors.initials: N
authors.lastname: Wilkie
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rosahl
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Laroque
authors.forename: Christine
authors.initials: C
authors.lastname: Boussiquet-Leroux
authors.forename: Ian
authors.initials: I
authors.lastname: Churcher
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C510791:MRK 560; D011480:Protease Inhibitors; D051880:Receptors, Notch; D013449:Sulfonamides; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases