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
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
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DOI：
10.1124/jpet.106.114330
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Shearman, Mark S.
中科院分区：
文献类型：
--
作者：
Best, Jonathan D.;Smith, David W.;Shearman, Mark S.
大量证据表明β-淀粉样肽（A β）是阿尔茨海默病（AD）发病和发展的关键因素。对抗AD的一种策略是通过抑制γ-分泌酶来减少或消除A β的产生，所述γ-分泌酶将A β从淀粉样前体蛋白（APP）裂解。我们在此证明，3 mg/kg强效、口服生物可利用和脑渗透性γ-分泌酶抑制剂N-[顺式-4-[（4-氯苯基）-磺酰基]-4-（2，5-二氟苯基）环己基]-1，1，1-三氟甲磺酰胺（MRK- 560）长期治疗3个月可减弱Tg 2576小鼠中淀粉样蛋白斑块的出现。这些斑块的减少也伴随着反应性神经胶质增生水平的降低。形态测量和组织学测量与皮质中A β（40）和A β（42）的生化分析一致。有趣的是，各治疗组的斑块体积没有变化，表明一旦开始，降低A β水平不会显著改变存款生长。此外，我们证明，这些有益的效果可以实现，而不会导致回肠，脾脏或胸腺的组织病理学变化的结果，阻断替代底物的加工，如Notch家族的受体。这表明在体内这些底物之间的治疗窗口似乎是可能的-这是开发这种AD方法的关键问题。对MRK- 560显示γ-分泌酶的APP和Notch蛋白水解途径之间差异的机制的理解应该为下一代γ-分泌酶抑制剂提供基础。
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.