Background: Gamma secretase is responsible for the intramembraneous cleavage of the Alzheimer's Precursor Protein (APP), the Notch receptor, and several other substrates. While inhibition of this protease results in potentially therapeutic reductions in the neurotoxic Abeta peptide, severe side effects might result from inhibiting Notch processing. We report a novel thiophene sulfonamide gamma-secretase inhibitor, GSI-953, that selectively inhibits cleavage of APP while sparing Notch processing. Methods: In vitro assays of Abeta production and Notch function, measurements of Abeta levels in plasma and brain of Tg2576 mouse, and assessments of cognitive function using the contextual fear conditioning model are described, as well as human plasma Abeta levels and initial biomarker data. Results: This compound inhibits Abeta production with low nM potency in vitro in cellular and cell-free assays. Cellular assays of Notch cleavage reveal that this compound is >15-fold selective for the inhibition of APP cleavage. In the Tg2576 transgenic mouse, this compound causes a robust reduction in brain and plasma Abeta levels and reverses memory deficits that are correlated with Abeta load. A lowering of plasma Abeta levels in human demonstrates target engagement. Conclusions: These data demonstrate that GSI-953 is a potent and selective gamma-secretase inhibitor with potential for therapeutic utility in Alzheimer's Disease. For these reasons, GSI-953 has been advanced into human clinical trials.
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