MEDI 11 |
| Glycine Transporter Type 1 (GlyT1) regulates synaptic glycine concentration in neurons and glial cells. According to the NMDA (N-Methyl-D-Aspartate Receptor) hypofuntion theory of the pathophysiology of schizophrenia, selective GlyT1 inhibitors may have therapeutic value in the treatement of psychoses. The 2-phenyl-cyclohexyl motif was identified as a privileged substructure during a high throughput screening campaign aimed at discovering novel GlyT1 inhibitors. This finding prompted us to attempt the synthesis of chymeric compounds, combining the novel structural element with the known 4-aminopiperidine scaffold. The resulting class of N(1)-(2-phenyl-cylohexyl)-4-amino-piperidine derivatives shows high potency, a selective pharmacological profile and promising molecular properties. In particular, improvement of the selectivity towards the GlyT2 transporter and the u-Opioid Receptor (MOR) was achieved compared to both parent structures. A broad SAR screen was performed and an optimal molecular property profile was achieved through introduction of a tertiary alcohol at position 2 of the 2-phenyl-cyclohexyl system.
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General Oral Session
9:00 AM-12:40 PM, Sunday, 10 September 2006 Moscone Center -- Room 102, Oral
Division of Medicinal Chemistry |
