The discovery of a structurally novel class of inhibitors of the type 1 glycine transporter

• Published in: Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.2974-2976
• Main Authors: Lowe, John A., Hou, Xinjun, Schmidt, Christopher, David Tingley, F., McHardy, Stan, Kalman, Monica, DeNinno, Shari, Sanner, Mark, Ward, Karen, Lebel, Lorraine, Tunucci, Don, Valentine, James
• Format: Article
• Language: English
• Subjects: [3.1.0]-Azabicyclic; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Biological and medical sciences; Cell Line; Drug Design; Glutamatergic system (aspartate and other excitatory aminoacids); Glycine; Glycine - metabolism; Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors; Glycine Plasma Membrane Transport Proteins - metabolism; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - pharmacology; Humans; Inhibitor; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NMDA; Pharmacology. Drug treatments; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; Structure-Activity Relationship; Transporter
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.035

The discovery of a potent, selective inhibitor of the type 1 glycine transporter, 10, is reported. The type 1 glycine transporter plays an important in regulating homeostatic glycine levels in the brain that are relevant to the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. We describe herein the structure–activity relationships (SAR) of a structurally novel class of GlyT1 inhibitors following on a lead derived from high throughput screening, which shows good selectivity for GlyT1 and potent activity in elevating CSF levels of glycine.