A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors

Bioorg Med Chem Lett. 2013 Feb 1;23(3):850-3. doi: 10.1016/j.bmcl.2012.11.054. Epub 2012 Nov 28.

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.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry*
  • Benzopyrans / pharmacology
  • Benzoquinones / chemical synthesis
  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Fluorine / chemistry
  • Fluorine / pharmacology
  • Humans
  • Molecular Structure
  • Oxidation-Reduction
  • Sulfones / chemical synthesis
  • Sulfones / chemistry*
  • Sulfones / pharmacology

Substances

  • Benzopyrans
  • Benzoquinones
  • Enzyme Inhibitors
  • SCH 900229
  • Sulfones
  • Fluorine
  • quinone
  • Amyloid Precursor Protein Secretases