Notes The authors declare no competing financial interest. Title: Gamma Secretase Modulators Application Number: WO 2013066740A1 Publication date: 10 May 2013 Priority Application: 61/553,384 Priority date: 31 October 2011 Inventors: W. Greenlee, D. Pissarnitski, Z. Zhao, Z. Zhu Assignee Company: Merck Sharpe & Dohme Disease Area: Neurodegeneration Biological Target: Gamma secretase Summary: Gamma secretase is an aspartic protease complex involved in the biosynthesis of Aβ peptide, a potential neurotoxic contributor in the progression of Alzheimer’s disease. Direct inhibition of enzymatic activity introduces potential selectivity issues associated with other biological functions of gamma secretase including Notch and Eph processing. As an alternative approach to gamma secretase inhibition, modulation of enzyme activity using, e.g., NSAIDs is a potentially druggable concept. This patent describes the synthesis and evaluation of a novel chemical series that demonstrates inhibition of gamma secretase activity in vitro and reduction of Aβ42 CSF levels following oral administration of a standard dose of 30 mg/kg. Primary Markush: