MRK-560 是一种口服有效的，可渗透血脑屏障的γ-Secretase抑制剂，能有效减少大鼠脑和脑脊液中 Aβ 肽。MRK-560 能通过选择性地抑制PSEN1来阻碍NOTCH1的突变进程。MRK-560 可用于阿尔兹海默病和 T 细胞急性淋巴细胞白血病的研究。
| 生物活性 | MRK-560 is an orally active, brain barrier-penetratingγ-Secretaseinhibitor, can potently reduces Aβ peptide in rat brain and cerebrospinal fluid. MRK-560 also decreases mutantNOTCH1processing by selectively inhibitingPSEN1. MRK-560 can be used in studies of Alzheimer's disease and T-cell acute lymphoblastic leukaemia (T-ALL)[1][2]. |
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体外研究
(In Vitro) | MRK-560 (30, 100, 300, 1000 nM; 15days) blocks mutant NOTCH1 receptor signaling in human T-ALL cell lines[1].
Cell Proliferation Assay[1] | Cell Line: | HPB-ALL, DND-41, and Jurkat cells | | Concentration: | 30, 100, 300, 1000 nM | | Incubation Time: | 15 days | | Result: | Reduced NICD1 generation in cells and resulted in a dose-dependent decrease of proliferation in HPB-ALL and DND-41, which depend on NOTCH signaling for their survival. |
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体内研究
(In Vivo) | MRK-560 (15.54 mg/kg; S.C.; single daily for 14 days) shows strong antileukemic effects on T-ALL model[1].
MRK-560 (1, 3, 10, 30, 100 mg/kg; p.o.; single) shows good blood-brain barrier permeability in a dose-dependent manner in rats[2].
MRK-560 (1, 3, 10, 30, 100 mg/kg; p.o.; single) inhibits the production of Aβ levels in brain and cerebrospinal fluid[2].
MRK-560 (1 mg/kg; p.o.; single) shows a good bioavailability of 70 to 90%, and Tmaxis 12 h[2].
MRK-560 (1 mg/kg; i.v.; single) is suitable for once-a-day dosing (with a low plasma clearance and a half-life of more than 15 h)[2].
| Animal Model: | Tg (HLA-DRB1) 31Dmz/Szj (NSG) mice (T-ALL (T cell acute lymphoblastic leukemia) model)[1]. | | Dosage: | 15.54 mg/kg | | Administration: | Subcutaneous injection; single daily for 14 days. | | Result: | Resulted in strong antileukemic effects and improved median survival to 30 days compared to 18 days in vehicle-treated mice. |
| Animal Model: | Male Sprague-Dawley rats (250-300 g)[2]. | | Dosage: | 1, 3, 10, 30, 100 mg/kg | | Administration: | Oral administration; single (experiment is performed 8 h later) | | Result: | Increased the plasma and brain concentrations in a dose-dependent manner.
Reduced (dose-dependent) both brain and CSF Aβ levels, with essentially complete inhibition of the production of both peptides being observed at a dose of 100 mg/kg. |
| Animal Model: | Male Sprague-Dawley rats (250-300 g)[2]. | | Dosage: | 1 mg/kg | | Administration: | Intravenously and orally administration; single. | | Result: | Showed Tmaxafter the oral dose was 12 h,and bioavailability was 70 to 90%.
Revealed a low plasma clearance of less than 5 mL/min/kg with a volume of distribution of approximately 6 L/kg, which translated to a long half-life of more than 15 h. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 100 mg/mL(193.08 mM;Need ultrasonic) 配制储备液 | 1 mM | 1.9308 mL | 9.6540 mL | 19.3080 mL | | 5 mM | 0.3862 mL | 1.9308 mL | 3.8616 mL | | 10 mM | 0.1931 mL | 0.9654 mL | 1.9308 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 |
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