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Updated: May 15, 2026

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors
Wen-Lian Wu1, Thavalakulamgara K Sasikumar, Martin S Domalski
1Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. wen-lian.wu@merck.com
Abstract:
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.
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