Begacestat (GSI-953) 是淀粉样前体蛋白 γ 分泌酶 (gamma-secretase) 的选择性噻吩磺酰胺抑制剂 (IC50Aβ40=15 nM)，有潜力用于阿尔兹海默症的研究。
Begacestat (5 mg/kg, p.o. in mice) treatment for 4 h significantly reduces the Aβ
40
and Aβ
42
in brain (37% lowering of brain Aβ
40
and 25% lowering of Aβ
40
observed).
Begacestat (GSI-953: 0, 2.5, 5, or 10 mg/kg, oral gavage, 3 h) results in a dose-dependent reversal of contextual fear conditioning deficits when compound is orally administered 3 h before training. Significant deficits are observed after treatment with 2.5 mg/kg Begacestat, and there is some reversal of this at 5 mg/kg and full reversal at 10 mg/kg compared with vehicle-dosed Tg2576 mice.
A dosage-related trend of slightly lower percentages of SP CD4+ cells in males at all dosages (SP CD4+ cells=~11% in controls compared with ~7% to ~9% in Begacestat-dosed animals) and females at 2000 mg/kg/day (SP CD4+ cells=~10% in controls compared with ~8% in Begacestat-dosed animals) is observed.
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Animal Model:
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Tg2576 mice
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Dosage:
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0, 2.5, 5, or 10 mg/kg
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Administration:
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Oral gavage for two consecutive days
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Result:
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Resulted in a dose-dependent reversal of contextual fear conditioning deficits when compound is orally administered 3 h before training.
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Animal Model:
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Sprague-Dawley rats
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Dosage:
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0, 200, 600, or 2000 mg/kg/day for 10 (5 males/group and 5 females at 600 mg/kg/day) or 28 (10/sex/group) consecutive days
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Administration:
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P.O. for 10 (5 males/group and 5 females at 600 mg/kg/day) or 28 (10/sex/group) consecutive days.
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Result:
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A dosage-related trend of slightly lower percentages of SP CD4+ cells in males at all dosages and females at 2000 mg/kg/day was observed.
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