Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors

Bioorg Med Chem Lett. 2013 Feb 1;23(3):844-9. doi: 10.1016/j.bmcl.2012.11.047. Epub 2012 Nov 24.

Abstract

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Cyclization
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyrans / chemical synthesis
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • Benzopyrans
  • Enzyme Inhibitors
  • Pyrans
  • SCH 900229
  • Sulfones
  • Amyloid Precursor Protein Secretases