An inhibitor of BACE
LY2886721 is an oral and furothiazine-based inhibitor of β site-amyloid protein cleaving enzyme (BACE) with IC50 of 20.3nM. This product has the potency for the treatment of Alzheimer's disease.
BACE, also known as Beta-Secretase 1, is an aspartic-acid protease that plays important role in the formation of myelin sheaths in peripheral nerve cells.
In vitro, treatment of LY2886721 leads to the inhibition of Aβ in HEK293Swe with IC50 of 18.7nM and PDAPP neuronal culture with IC50 10.7 nM1. LY2886721 decreases CSF sAPPβ and increases CSF sAPPα in a dose- dependent manner 2.
In PDAPP mice, oral administration of LY2886721 resulted in a reduction in brain Aβ, C99 and sAPPβ in a dose-dependent pattern 2. Aβ levels in the brain were decreased by 20% -65% as compared with the vehicle-treated groups 3 hours after treatment of LY2886721 at a dosage of 3-30 mg/kg per mice. In addition, LY2886721 significantly lowers plasma and CSF Aβs in the MAD study 1.
参考文献:
1.? Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimer's research & therapy. 2014;6(9):89.
2.?? Nishitomi K, Sakaguchi G, Horikoshi Y, et al. BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. Journal of neurochemistry. 2006;99(6):1555-1563.
| Animal experiment [1]: | |
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Animal models |
PDAPP mice |
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Dosage form |
3, 10 or 30 mg/kg; p.o. |
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Applications |
At all 3 doses, LY2886721 significantly reduced hippocampal and cortical levels of Aβ1-x. In addition, LY2886721 significantly lowered brain parenchymal levels of C99 and sAPPβ. Although cortical levels of C99 were reduced significantly by LY2886721 at the doses of 10 and 30 mg/kg, the effect of LY2886721 at the dose of 3 mg/kg failed to reach statistical significance. On the other hand, the sAPPβ levels were significantly decreased by LY2886721 at all 3 doses. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, Audia JE, Boggs LN, Borders AR, Brier RA, Calligaro DO, Day TA, Ereshefsky L, Erickson JA, Gevorkyan H, Gonzales CR, James DE, Jhee SS, Komjathy SF, Li L, Lindstrom TD, Mathes BM, Martényi F, Sheehan SM, Stout SL, Timm DE, Vaught GM, Watson BM, Winneroski LL, Yang Z, Mergott DJ. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015 Jan 21;35(3):1199-210. | |
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