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

This overall aim of this study was to determine the effects of chronic dosing of MRK-560 on Abeta levels and beta-amyloid plaque formation in the Tg2576 mouse model of amyloid deposition. In addition,  peripheral tissues were examined histologically for signs of toxicity that may be related to altered Notch signaling. Results found that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant gamma-secretase inhibitor MRK-560 attenuated the appearance of beta-amyloid plaques in the Tg2576 mouse. The 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. Furthermore, the data demonstrated 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. These data suggest 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 by which 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.