bms-299897

Description: BMS 299897 is a novel and potent sulfonamide gamma-secretase inhibitor with an IC50 of 7 nM for Abeta production inhibition in HEK293 cells stably overexpressing amyloid precursor protein (APP). BMS-299897 blocked the increase in Abeta(1-42) content and decreased Abeta(1-40) levels significantly. The compound did not affect Abeta(25-35)-induced increase in hippocampal lipid peroxidation. Behaviorally, BMS-299897 blocked the Abeta(25-35)-induced deficits in spontaneous alternation or novel object recognition, using a 1h intertrial time interval. BMS-299896 failed to affect the passive avoidance impairments or novel object recognition, using a 24h intertrial time interval. These results confirmed that Abeta(25-35) injection provoked an accumulation in endogenous Abeta(1-42), an effect blocked by gamma-secretase inhibition. This Abeta(1-42) accumulation marginally contributed to the toxicity or long-term memory deficits. However, since the seeded Abeta(1-42) affected short-term memory, the rapid Abeta(25-35) injection Alzheimer's disease model could be used to screen the activity of new secretase inhibitors.

References: PLoS One. 2015 Feb 24; 10(2):e0118379; Eur J Pharmacol. 2013 Jan 5; 698(1-3):193-9.