Tricyclic sulfones as orally active gamma-secretase inhibitors: synthesis and structure-activity relationship studies

T K Sasikumar; Li Qiang; Duane A Burnett; David Cole; Ruo Xu; Hongmei Li; William J Greenlee; John Clader; Lili Zhang; Lynn Hyde

doi:10.1016/j.bmcl.2010.04.104

Tricyclic sulfones as orally active gamma-secretase inhibitors: synthesis and structure-activity relationship studies

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3632-5. doi: 10.1016/j.bmcl.2010.04.104. Epub 2010 May 5.

Authors

T K Sasikumar¹, Li Qiang, Duane A Burnett, David Cole, Ruo Xu, Hongmei Li, William J Greenlee, John Clader, Lili Zhang, Lynn Hyde

Affiliation

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

PMID: 20493690
DOI: 10.1016/j.bmcl.2010.04.104

Abstract

Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.

MeSH terms

Administration, Oral
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / blood
Animals
Brain Chemistry / drug effects
Mice
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology
Sulfones / chemical synthesis
Sulfones / chemistry*
Sulfones / pharmacology*

Substances

Amyloid beta-Peptides
Protease Inhibitors
Sulfonamides
Sulfones
Amyloid Precursor Protein Secretases