Pharmacological properties of a novel and potent γ-secretase modulator as a therapeutic option for the treatment of Alzheimer's disease

Previous studies of gamma-secretase inhibitors (GSIs) and Notch-sparing GIs have shown reduced amyloid-beta (A beta) peptide levels but increased Notch-related and-unrelated adverse effects. In this study, we examined the effects of compound-1 on A beta processing and cognitive function and assessed Notch-related and-unrelated adverse effects. Compound 1 reduced A beta 40 and A beta 42 levels but inversely increased A beta 37 in Neuro2a cells, leading to no net changes in total A beta levels, indicating that compound-1 is a gamma-secretase modulator (GSM). In time-course experiments, compound-1 reduced A beta 40 and A beta 42 levels in trissoluble fractions, with peak reduction at approximately 3 h after oral administration in C57BL mice. Moreover, at >1 mg/kg, compound-1 dose dependently reduced A beta 40 and A beta 42 levels in Tg2576 mice. Chronic treatment with compound-1 in Tg2576 mice for 4 months significantly reduced both soluble and insoluble A beta 42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 months. In contrast with compound-1, at 100-fold higher doses (100 mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover, the Notch sparing GSI BMS708163 led to amyloid precursor protein (APP)-beta-C-terminal fragment accumulation in mouse primary neurons. BMS708163 significantly hampered cognitive function in normal mice 1 month after administration, whereas compound-1 significantly improved cognitive function. Taken together, the present novel and orally active GSM is a promising molecule for the treatment of pathologies associated with A beta 42 and A beta 40. (c) 2016 Elsevier B.V. All rights reserved.