MRK 560

γ-secretase inhibitor CAS# 677772-84-8

MRK 560

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MRK 560

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Chemical Properties of MRK 560

Cas No. 677772-84-8 SDF Download SDF
PubChem ID 11577204 Appearance Powder
Formula C19H17ClF5NO4S2 M.Wt 517.92
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO and to 50 mM in ethanol
Chemical Name N-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide
SMILES C1CC(CCC1NS(=O)(=O)C(F)(F)F)(C2=C(C=CC(=C2)F)F)S(=O)(=O)C3=CC=C(C=C3)Cl
Standard InChIKey WDZVWDXOIGQJIO-UHFFFAOYSA-N
Standard InChI InChI=1S/C19H17ClF5NO4S2/c20-12-1-4-15(5-2-12)31(27,28)18(16-11-13(21)3-6-17(16)22)9-7-14(8-10-18)26-32(29,30)19(23,24)25/h1-6,11,14,26H,7-10H2
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MRK 560

Descriptionγ-secretase inhibitor; inhibits proteolytic cleavage of amyloid precursor protein (APP) over the Notch pathway. Reduces levels of Aβ in the brain (inhibits Aβ40 and Aβ42 in SH-SY5Y neuroblastoma cells with an IC50 of 0.65 nM); attenuates plaque deposition. Orally bioavailable.

MRK 560 Dilution Calculator

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Preparing Stock Solutions of MRK 560

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9308 mL 9.654 mL 19.308 mL 38.616 mL 48.27 mL
5 mM 0.3862 mL 1.9308 mL 3.8616 mL 7.7232 mL 9.654 mL
10 mM 0.1931 mL 0.9654 mL 1.9308 mL 3.8616 mL 4.827 mL
50 mM 0.0386 mL 0.1931 mL 0.3862 mL 0.7723 mL 0.9654 mL
100 mM 0.0193 mL 0.0965 mL 0.1931 mL 0.3862 mL 0.4827 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on MRK 560

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.

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References on MRK 560

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-trifl uoromethanesulfonamide (MRK-560) in the rat.[Pubmed:16443723]

J Pharmacol Exp Ther. 2006 May;317(2):786-90.

Plaques in the parenchyma of the brain containing Abeta peptides are one of the hallmarks of Alzheimer's disease. These Abeta peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease gamma-secretase. Thus, one approach to lowering levels of Abeta has been via the inhibition of the gamma-secretase enzyme. Here, we report a novel, bioavailable gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifl uoromethanesulfonamide (MRK-560) that displayed oral pharmacokinetics suitable for once-a-day dosing. It was able to markedly reduce Abeta in the brain and cerebrospinal fluid (CSF) in the rat, with ED(50) values of 6 and 10 mg/kg, respectively. Time-course experiments using MRK-560 demonstrated these reductions in Abeta could be maintained for 24 h, and comparable temporal reductions in rat brain and CSF Abeta(40) further suggested that these two pools of Abeta are related. This relationship between the brain and CSF Abeta was maintained when MRK-560 was dosed once a day for 2 weeks, and accordingly, when all the data for the dose-response curve and time courses were correlated, a strong association was observed between the brain and CSF Abeta levels. These results demonstrate that MRK-560 is an orally bioavailable gamma-secretase inhibitor with the ability to markedly reduce Abeta peptide in the brain and CSF of the rat and confirm the utility of the rat for assessing the effects of gamma-secretase inhibitors on central nervous system Abeta(40) levels in vivo.

The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifl uoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse.[Pubmed:17099072]

J Pharmacol Exp Ther. 2007 Feb;320(2):552-8.

There is a substantial body of evidence indicating that beta-amyloid peptides (Abeta) 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 Abeta through inhibition of the gamma-secretase enzyme, which cleaves Abeta 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-trif luoromethanesulfonamide (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 Abeta(40) and Abeta(42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing Abeta 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.

Quantitative assessment of Abeta peptide in brain, cerebrospinal fluid and plasma following oral administration of gamma-secretase inhibitor MRK-560 in rats.[Pubmed:25567290]

Int J Neurosci. 2015;125(8):616-24.

The beta-amyloid peptides (Abeta) are thought to play a critical role in the pathophysiology of Alzheimer's disease. One therapeutic strategy aimed to reduce or eliminate the production of Abeta peptides is inhibition of the gamma-secretase enzyme, which cleaves amyloid precursor protein to form Abeta peptides. We studied the in vivo effects of the potent, orally bioavailable and brain penetrant gamma-secretase inhibitor (GSI), MRK-560, on both Abetax-40 and Abetax-42 in multiple compartments (plasma, the brain and cerebrospinal fluid) of rat. Although there were differences in the time course and magnitude of the changes, the results showed that MRK-560 caused marked inhibition of both Abetax-40 and Abetax-42 in all three compartments. We identified good correlations between plasma Abetax-40 versus brain Abetax-40 (r = 0.84), and plasma Abetax-40 versus CSF Abetax-40 (r = 0.85), indicating that these pools of Abeta are related dynamically. These results suggest that central Abeta changes that occur following acute dosing with MRK-560 can be predicted based on plasma Abeta changes and could thus serve as a useful biomarker to help accelerate decision-making during early clinical development.

Decreased axonal transport rates in the Tg2576 APP transgenic mouse: improvement with the gamma-secretase inhibitor MRK-560 as detected by manganese-enhanced MRI.[Pubmed:22958226]

Eur J Neurosci. 2012 Nov;36(9):3165-72.

Neuropil deposition of beta-amyloid (Abeta) peptides is believed to be a key event in the neurodegenerative process of Alzheimer's disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trif luoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30 mumol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of Abeta found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of Abeta were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of Abeta, and fully reverses the axonal transport dysfunction.

Description

MRK-560 is a potent, orally bioavailable and brain-penetrant γ-secretase inhibitor.

Keywords:

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