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

Bence Szilágyi, G. Ferenczy, György M. Keserű

Research output: Contribution to journalReview article

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)973-982
Number of pages10
JournalExpert Opinion on Drug Discovery
Volume13
Issue number10
DOIs
Publication statusPublished - Oct 3 2018

Fingerprint

D-Amino-Acid Oxidase
Drug Discovery
Antipsychotic Agents
Serine
Schizophrenia
Therapeutics
Carboxylic Acids
Pharmacokinetics
Neurobehavioral Manifestations
Aptitude
Expert Testimony
N-Methyl-D-Aspartate Receptors
Animal Models

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies. / Szilágyi, Bence; Ferenczy, G.; Keserű, György M.

In: Expert Opinion on Drug Discovery, Vol. 13, No. 10, 03.10.2018, p. 973-982.

Research output: Contribution to journalReview article

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