IC50: 0.65 nM for both Aβ(40) and Aβ(42)
MRK-560 is a novel γ-secretase inhibitor.
γ-Secretase is a member of the I-CLiP protease family and is reported to cleave a number of additional intramembrane substrates, including Erb4, CD-44, Notch, E-cadherin, and the Notch ligands. γ-Secretase is responsible for the intramembraneous proteolytic cleavage of the C-terminal fragment of APP, resulting in mainly Aβ(40) or Aβ(42) production.
In vitro: 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].
In vivo: 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].
Clinical trial: N/A
Reference:
[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.