Progress in the Exploration and Development of GlyT1 Inhibitors for Schizophrenia

Albert, Jeffrey S.; Wood, Michael W.

doi:10.1002/9781118309421.ch8

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“…Given the obligatory role glycine plays in NMDA activation, it is not surprising that pharmacological manipulation of synaptic glycine levels via GlyT1 inhibition has been an active area of pharmaceutical research. Several GlyT1 antagonists have been described in the literature. − The first generation of GlyT1 inhibitors were predominantly sarcosine analogs (e.g., 1 and 2 ) (Figure ) with initial in vitro profiles that appeared promising. However, further investigation showed that many of these sarcosine derivatives produced a range of deleterious side effects including ataxia, lateral recumbency, and respiratory depression. , These side effects are likely the result of sustained elevation of glycine in caudal regions of the CNS, where GlyT1 and the glycine receptor (Gly A sites) are colocalized and play an important role in control of motor function and respiration. , More recent efforts to develop GlyT1 inhibitors have focused on non-sarcosine chemotypes.…”

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confidence: 99%

Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

et al. 2018

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We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

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