Triazoloamides as potent γ-secretase modulators with reduced hERG liability

Christian Fischer; Susan L Zultanski; Hua Zhou; Joey L Methot; Sanjiv Shah; Hugh Nuthall; Bethany L Hughes; Nadja Smotrov; Armetta Hill; Alexander A Szewczak; Christopher M Moxham; Nathan Bays; Richard E Middleton; Benito Munoz; Mark S Shearman

doi:10.1016/j.bmcl.2012.03.054

Triazoloamides as potent γ-secretase modulators with reduced hERG liability

Bioorg Med Chem Lett. 2012 May 1;22(9):3140-6. doi: 10.1016/j.bmcl.2012.03.054. Epub 2012 Mar 21.

Authors

Christian Fischer¹, Susan L Zultanski, Hua Zhou, Joey L Methot, Sanjiv Shah, Hugh Nuthall, Bethany L Hughes, Nadja Smotrov, Armetta Hill, Alexander A Szewczak, Christopher M Moxham, Nathan Bays, Richard E Middleton, Benito Munoz, Mark S Shearman

Affiliation

¹ Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. christian_fischer@merck.com

PMID: 22497762
DOI: 10.1016/j.bmcl.2012.03.054

Abstract

Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC(50) in cell-based assays and reduced affinity for the hERG channel.

MeSH terms

Amides / chemistry
Amides / pharmacology
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides
Cell Line
Dose-Response Relationship, Drug
Humans
Inhibitory Concentration 50
Lactams
Structure-Activity Relationship
Trans-Activators / metabolism*
Transcriptional Regulator ERG
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Amides
Amyloid beta-Peptides
ERG protein, human
Lactams
Trans-Activators
Transcriptional Regulator ERG
Triazoles
Amyloid Precursor Protein Secretases