(S)-N-(5-Chlorothiophene-2-sulfonyl)-β,β-diethylalaninol a Notch-1-sparing γ-secretase inhibitor

Abstract Accumulation of beta-amyloid (Aβ), produced by the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretase, is widely believed to be associated with Alzheimer’s disease (AD). Research around the high-throughput screening hit ( S )-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) γ-secretase inhibitor ( S )- N -(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol 7.b.2 (Aβ 40/42 EC 50  = 28 nM), which is efficacious in reduction of Aβ production in vivo.