GlyT1 has widespread distribution in forebrain areas such as the cortex and hippocampus and is thought to be co-localized with the NMDA receptor, controlling NMDA receptor function. Medications which inhibit GlyT1 activity and thereby induce NMDA receptor function may be useful as therapeutic agents for treating schizophrenia, dementia, and other related disorders.To identify selective GlyT1 inhibitors, we synthesized a series of 4H-1,2,4-triazole derivatives derived from high-throughput screening. Structure-activity relationship (SAR) exploration afforded a benzonitrile analogue with potent and selective GlyT1 inhibitory activity. The restricted rotation at the C-N bond between triazole and benzonitrile provided thermally stable atropisomers at ambient temperatures. We successfully separated the atropisomers and found that (-)-3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile has 460-fold selectivity between GlyT1 and GlyT2. Here, we describe the SAR and synthesis of the (-)-atropisomer, including optical resolution, as well as detail its in vivo pharmacological profile.

Synthesis and biological evaluation of 1,2,4-triazole derivatives as selective glycine transporter 1 (GlyT1) inhibitors

241st National Meeting (2011)

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