Cyclic sulfamide gamma-secretase inhibitors

Bioorg Med Chem Lett. 2005 Oct 1;15(19):4212-6. doi: 10.1016/j.bmcl.2005.06.084.

Abstract

A novel series of N-alkyl-substituted cyclic sulfamides were developed from a screening hit. Chemistries were developed which allowed surveys of N-alkyl groups and amines resulting in the identification of N-trifluoroethyl-substituted cyclic sulfamides with good in vitro and in vivo gamma-secretase activity. One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases
  • Brain Chemistry
  • Endopeptidases
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology
  • Inhibitory Concentration 50
  • Mice
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis*
  • Sulfonic Acids / pharmacology

Substances

  • Amyloid beta-Peptides
  • Heterocyclic Compounds
  • Protease Inhibitors
  • Sulfonic Acids
  • sulfamic acid
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse