The novel γ 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

被引:80
作者
Best, Jonathan D.
Smith, David W.
Reilly, Michael A.
O'Donnell, Ruth
Lewis, Huw D.
Ellis, Semantha
Wilkie, Neil
Rosahl, Thomas W.
Laroque, Philippe A.
Boussiquet-Leroux, Christine
Churcher, Ian
Atack, John R.
Harrison, Timothy
Shearman, Mark S.
机构
[1] Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Dept Vivo Neurosci, Harlow CM20 2QR, Essex, England
[2] Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Dept Mol & Cellular Neurosci, Harlow CM20 2QR, Essex, England
[3] Merck Sharp & Dohme Res Ctr, Dept Safety Assessment, Clermont Ferrand, France
关键词
D O I
10.1124/jpet.106.114330
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
There is a substantial body of evidence indicating that beta-amyloid peptides ( A beta) 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 A beta through inhibition of the gamma- secretase enzyme, which cleaves A beta 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 A beta( 40) and A beta( 42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing A beta 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.
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页码:552 / 558
页数:7
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