ABSTRACT
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.