Design and synthesis of a novel series of cyanoindole derivatives as potent γ-secretase modulators

François P Bischoff; Adriana Ingrid Velter; Garrett Minne; Serge Pieters; Didier Berthelot; Michel De Cleyn; Harrie J M Gijsen; Gregor Macdonald; Michel Surkyn; Sven Van Brandt; Yves Van Roosbroeck; Chiara Zavattaro; Marc Mercken; Nigel Austin; Deborah Dhuyvetter; Herman Borghys; Ishtiyaque Ahmad; Swapan Kumar Samanta

doi:10.1016/j.bmcl.2019.05.023

Design and synthesis of a novel series of cyanoindole derivatives as potent γ-secretase modulators

Bioorg Med Chem Lett. 2019 Jul 15;29(14):1737-1745. doi: 10.1016/j.bmcl.2019.05.023. Epub 2019 May 15.

Authors

François P Bischoff¹, Adriana Ingrid Velter², Garrett Minne², Serge Pieters², Didier Berthelot², Michel De Cleyn², Harrie J M Gijsen², Gregor Macdonald², Michel Surkyn², Sven Van Brandt², Yves Van Roosbroeck², Chiara Zavattaro², Marc Mercken², Nigel Austin², Deborah Dhuyvetter², Herman Borghys², Ishtiyaque Ahmad³, Swapan Kumar Samanta³

Affiliations

¹ Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: [email protected].
² Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
³ Jubilant Biosys Ltd, Bangalore, Karnataka, India.

PMID: 31122869
DOI: 10.1016/j.bmcl.2019.05.023

Abstract

The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.

Keywords: Alzheimer’s disease; GSMs; γ-Secretase; γ-Secretase modulators.

MeSH terms

Amyloid Precursor Protein Secretases / metabolism*
Drug Design
Humans
Indoles / chemical synthesis*
Structure-Activity Relationship

Substances

Indoles
indole
Amyloid Precursor Protein Secretases