title: Triazoloamides as potent γ-secretase modulators with reduced hERG liability.
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.
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. christian_fischer@merck.com
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.forename: Susan L
authors.initials: SL
authors.lastname: Zultanski
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.forename: Hugh
authors.initials: H
authors.lastname: Nuthall
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.forename: Nadja
authors.initials: N
authors.lastname: Smotrov
authors.forename: Armetta
authors.initials: A
authors.lastname: Hill
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Moxham
authors.forename: Nathan
authors.initials: N
authors.lastname: Bays
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; C072312:ERG protein, human; D007769:Lactams; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases