ABSTRACT
Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aß42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aß42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aß42 levels.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Drug Discovery , Macaca mulatta , Mice , Mice, Transgenic , Rats , Rats, Sprague-DawleyABSTRACT
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Triazoles/chemical synthesis , Triazoles/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/metabolismABSTRACT
Synthesis, SAR and evaluation of styrenyl quinazolinones as novel gamma secretase modulators are presented in this communication. Starting from literature and in-house leads we evaluated a range of quinazolinones which showed good modulation of γ-secretase activity.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Quinazolinones/chemistry , Quinazolinones/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Cell Line , Humans , Inhibitory Concentration 50 , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Protein Binding , Quinazolinones/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
