Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies

ABSTRACT

Introduction: D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia.

Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility. Inhibitory potency and pharmacokinetic properties are discussed in the context of compounds’ ability to increase D-serine level and to show efficacy in animal models of schizophrenia.

Expert opinion: The accumulated knowledge on the structural requirements of DAAO inhibitors and on their in vitro and in vivo effects provides appropriate basis to develop inhibitors with optimized potency, selectivity and pharmacokinetic profile including blood-brain penetration. In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.

KEYWORDS:

• D-amino-acid oxidase
• D-serine
• schizophrenia

Article Highlights

• D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative and cognitive symptoms of schizophrenia.

• DAAO inhibition increases D-serine level in rodents and it is effective in animal models of schizophrenia.

• Differences were found in the effect of DAAO inhibitors on the D-serine level in rodents versus in dog and monkey.

• Further basic research is urged to explore the regional and cellular distribution of DAAO activity, the role of DAAO in neural pathways and the metabolic pathways of D-serine in order to validate DAAO as a drug target for schizophrenia.

• DAAO inhibitors with a wide range of properties have been identified and thoroughly characterized. Inhibitors with advantageous drug-like properties have been developed.

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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.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the National Brain Research Program [grant number KTIA NAP_13-2014-0009].