Anilinotriazoles as potent gamma secretase modulators

Adriana I Velter; François P Bischoff; Didier Berthelot; Michel De Cleyn; Daniel Oehlrich; Libuse Jaroskova; Gregor Macdonald; Garrett Minne; Serge Pieters; Frederik Rombouts; Sven Van Brandt; Yves Van Roosbroeck; Michel Surkyn; Andrés A Trabanco; Gary Tresadern; Tongfei Wu; Herman Borghys; Marc Mercken; Chantal Masungi; Harrie Gijsen

doi:10.1016/j.bmcl.2014.10.024

Anilinotriazoles as potent gamma secretase modulators

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5805-5813. doi: 10.1016/j.bmcl.2014.10.024. Epub 2014 Oct 18.

Authors

Adriana I Velter¹, François P Bischoff², Didier Berthelot², Michel De Cleyn², Daniel Oehlrich², Libuse Jaroskova³, Gregor Macdonald², Garrett Minne², Serge Pieters², Frederik Rombouts², Sven Van Brandt², Yves Van Roosbroeck², Michel Surkyn², Andrés A Trabanco⁴, Gary Tresadern³, Tongfei Wu², Herman Borghys³, Marc Mercken², Chantal Masungi³, Harrie Gijsen⁵

Affiliations

¹ Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: [email protected].
² Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
³ Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
⁴ Neuroscience, Janssen Research & Development, Jarama 75, 45007 Toledo, Spain.
⁵ Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: [email protected].

PMID: 25454273
DOI: 10.1016/j.bmcl.2014.10.024

Abstract

The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.

Keywords: Alzheimer’s disease; Anilinotriazoles; Gamma secretase modulators.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / chemistry
Amyloid beta-Peptides / metabolism
Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry*
Aniline Compounds / metabolism
Animals
Brain / metabolism
Drug Design
Humans
Mice
Mice, Transgenic
Protein Binding
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / metabolism

Substances

Amyloid beta-Peptides
Aniline Compounds
Triazoles
Amyloid Precursor Protein Secretases
aniline