Begacestat

Begacestat (GSI-953) is a selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase (IC50Aβ40=15 nM) for the treatment of Alzheimer's disease[1].

Research Areas >> Neurological Disease

IC50: 15 nM (Aβ40)[1].

Begacestat (5 mg/kg, p.o. in mice) treatment for 4 h significantly reduces the Aβ40 and Aβ42 in brain (37% lowering of brain Aβ40 and 25% lowering of Aβ40 observed)[1]. 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[2]. 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[2]. Animal Model: Tg2576 mice[2] Dosage: 0, 2.5, 5, or 10 mg/kg Administration: Oral gavage for two consecutive days Result: Resulted in a dose-dependent reversal of contextual fear conditioning deficits when compound is orally administered 3 h before training. Animal Model: Sprague-Dawley rats[2] Dosage: 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 Administration: P.O. for 10 (5 males/group and 5 females at 600 mg/kg/day) or 28 (10/sex/group) consecutive days. Result: 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.

[1]. Mayer SC, et al. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease. J Med Chem. 2008 Dec 11;51(23):7348-51.

[2]. Martone RL, et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther. 2009 Nov;331(2):598-608.