MRK-560 is a potent inhibitor of γ-secretase (IC50 = 0.65 nM). In vivo, MRK-560 (1-10 mg/kg) reduces diethanolamine-soluble amyloid-β (1-40) (Aβ40) levels in APP-YAC transgenic mouse brain. MRK-560 reduces brain and cerebrospinal fluid Aβ40 levels in rats (ED50s = 6 and 10 mg/kg, respectively). It also decreases brain-soluble Aβ40 and Aβ42 levels and recovers hippocampal long-term potentiation in the Tg2576 transgenic mouse model of Alzheimer''s disease.
MRK 560 acts as a y-secretase inhibitor that is orally bioavailable and potent and may be used in a therapeutic strategy to counter low amyloid (β) production in Alheimer’s disease.
in sh-sy5y neuroblastoma cells, mrk-560 inhibited the production of aβ(40) and aβ(42) with similar in vitro ic50 values in the range of 0.65 nm [1].
mrk-560 was found to be able to reduce aβ in the brain and cerebrospinal fluid (csf) in the rat markedly, with ed50s of 6 and 10 mg/kg, respectively. time-course experiments demonstrated the reductions in aβ could be maintained for 24 h. comparable temporal reductions in rat brain and csf further suggested that these two pools of aβ were related. such relationship between the brain and csf aβ was maintained when mrk-560 was dosed once a day for 2 weeks. these results indicated that mrk-560 was a γ-secretase inhibitor with the ability to reduce aβ peptide in the rat brain and csf [1].
0.65 nm for both aβ(40) and aβ(42)
[1] best jd,jay mt,otu f,churcher i,reilly m,morentin-gutierrez p,pattison c,harrison t,shearman ms,atack jr. in vivo characterization of abeta(40) changes in brain and cerebrospinal fluid using the novel gamma-secretase inhibitor n-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (mrk-560) in the rat. j pharmacol exp ther.2006 may;317(2):786-90.
