Glycine transporter-1 inhibitors: a patent review (2011–2016)

ABSTRACT

Introduction: Numerous research groups have developed GlyT-1 inhibitors in the pursuit of providing a novel antipsychotic treatment for schizophrenia. Despite multiple compounds advancing into clinical trials, a GlyT-1 inhibitor has yet to emerge to treat patients. However, the approach remains heavily investigated as it presents potential therapeutic utility for several other CNS and non-CNS-related indications.

Areas covered: This review discusses various GlyT-1 inhibitor chemotypes identified and provides an overview of patent applications filed and published during the period of 2011–2016. The review largely focuses on composition of matter patent applications, although two recently disclosed method of use patents are discussed. Clinical reports are also disseminated.

Expert opinion: Mounting clinical failures with schizophrenic patients have blunted enthusiasm for GlyT-1 inhibition as an approach to treat the disease. However, research in the area remains quite active, as therapeutic potential for several additional indications has emerged. There are numerous and diverse GlyT-1 chemotypes now available that exhibit differentiating modes of binding and ligand-target binding kinetics, and this rich diversity of chemical matter may help further elucidate the target’s pharmacological role in various indications and lead to the identification of a compound with optimal properties that may someday become a drug.

KEYWORDS:

• Glycine
• NMDA receptor
• glycine receptor
• sarcosine
• GlyR
• glycine transporter
• GlyT-1

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Corrigendum

Article highlights

• Recent Phase III clinical studies with GlyT-1 inhibitors have yielded disappointing outcomes for schizophrenic patients. These clinical failures have blunted enthusiasm for the target as a therapeutic intervention point for treating schizophrenia.

• Several recently published composition of matter patent applications have focused on chemically diverse non-sarcosine-based GlyT-1 inhibitors, many of which were initially identified from HTS campaigns. Numerous applications also claim scaffolds derived via ligand-based and/or scaffold hopping drug design approaches utilizing existing chemical matter.

• Two new method of use patents for an existing GlyT-1 inhibitor have also been published claiming therapeutic utility for the treatment of hematological disorders and pain.

• GlyT-1 inhibition has shown therapeutic potential for a diverse array of CNS and non-CNS-related indications beyond schizophrenia.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

The author did not receive any financial support for the preparation of this manuscript.