Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity

Ruo Xu; David Cole; Ted Asberom; Tom Bara; Chad Bennett; Duane A Burnett; John Clader; Martin Domalski; William Greenlee; Lynn Hyde; Hubert Josien; Hongmei Li; Mark McBriar; Brian McKittrick; Andrew T McPhail; Dmitri Pissarnitski; Li Qiang; Murali Rajagopalan; Thavalakulamgar Sasikumar; Jing Su; Haiqun Tang; Wen-Lian Wu; Lili Zhang; Zhiqiang Zhao

doi:10.1016/j.bmcl.2010.02.080

Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2591-6. doi: 10.1016/j.bmcl.2010.02.080. Epub 2010 Feb 23.

Affiliation

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

PMID: 20236824
DOI: 10.1016/j.bmcl.2010.02.080

Abstract

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Animals
Crystallography, X-Ray
Drug Design
Mice
Models, Molecular
Receptors, Notch / drug effects*
Sulfones / chemical synthesis
Sulfones / chemistry*
Sulfones / pharmacology*

Substances

Receptors, Notch
Sulfones
Amyloid Precursor Protein Secretases