Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions

Jing Su; Haiqun Tang; Brian A McKittrick; Ruo Xu; John W Clader; William J Greenlee; Lynn Hyde; Lili Zhang

doi:10.1016/j.bmcl.2011.03.094

Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3447-51. doi: 10.1016/j.bmcl.2011.03.094. Epub 2011 Apr 5.

Authors

Jing Su¹, Haiqun Tang, Brian A McKittrick, Ruo Xu, John W Clader, William J Greenlee, Lynn Hyde, Lili Zhang

Affiliation

¹ Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. [email protected]

PMID: 21515050
DOI: 10.1016/j.bmcl.2011.03.094

Abstract

SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / metabolism
Animals
Cyclization
Disease Models, Animal
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Inhibitory Concentration 50
Mice
Molecular Structure
Peptide Fragments / metabolism
Structure-Activity Relationship
Sulfones / chemical synthesis*
Sulfones / chemistry
Sulfones / pharmacology*

Substances

Amyloid beta-Peptides
Enzyme Inhibitors
Peptide Fragments
Sulfones
amyloid beta-protein (1-40)
Amyloid Precursor Protein Secretases