ABSTRACT
Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.
Subject(s)
Alzheimer Disease , tau Proteins , Humans , tau Proteins/metabolism , Alzheimer Disease/metabolism , Brain/metabolism , Neurofibrillary Tangles/metabolism , Neurofibrillary Tangles/pathology , PhosphorylationABSTRACT
3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.
ABSTRACT
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Animals , Cell Membrane Permeability , Drug Discovery , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Glycine Plasma Membrane Transport Proteins/analysis , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Mice , Rats , Solubility , Structure-Activity RelationshipABSTRACT
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
