Tetracyclic sulfones as potent gamma-secretase inhibitors: synthesis and structure-activity relationship studies

T K Sasikumar; Duane A Burnett; Theodros Asberom; Wen-Lian Wu; Chad Bennett; David Cole; Ruo Xu; William J Greenlee; John Clader; Lili Zhang; Lynn Hyde

doi:10.1016/j.bmcl.2010.04.103

Tetracyclic sulfones as potent gamma-secretase inhibitors: synthesis and structure-activity relationship studies

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3645-8. doi: 10.1016/j.bmcl.2010.04.103. Epub 2010 Apr 28.

Authors

T K Sasikumar¹, Duane A Burnett, Theodros Asberom, Wen-Lian Wu, Chad Bennett, David Cole, Ruo Xu, William J Greenlee, John Clader, Lili Zhang, Lynn Hyde

Affiliation

¹ Merck Research Laboratories, Kenilworth, NJ 07033, USA. [email protected]

PMID: 20471254
DOI: 10.1016/j.bmcl.2010.04.103

Abstract

Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / antagonists & inhibitors
Animals
Drug Design
Hepatocytes / metabolism
Humans
Mice
Protease Inhibitors / chemical synthesis*
Stereoisomerism
Structure-Activity Relationship
Sulfones / chemical synthesis
Sulfones / chemistry*
Sulfones / pharmacology

Substances

Amyloid beta-Peptides
Protease Inhibitors
Sulfones
Amyloid Precursor Protein Secretases