Assessment of the target engagement and d-serine biomarker profiles of the d-amino acid oxidase inhibitors sodium benzoate and PGM030756

Eimear Howley, Michael Bestwick, Rosa Fradley (Lead / Corresponding author), Helen Harrison, Mathew Leveridge, Kengo Okada, Charlotte Fieldhouse, Will Farnaby, Hannah Canning, Andy P. Sykes, Kevin Merchant, Katherine Hazel, Catrina Kerr, Natasha Kinsella, Louise Walsh, David G. Livermore, Isaac Hoffman, Jonathan Ellery, Phillip Mitchell, Toshal PatelMark Carlton, Matt Barnes, David J. Miller

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Irregular N-methyl-d-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and d-serine. One approach to activate the co-agonist site is to increase synaptic d-serine levels through inhibition of d-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other d-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer’s disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar d-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar d-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer’s disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and d-serine increases following administration of low oral doses.

Original languageEnglish
Pages (from-to)3279-3288
Number of pages10
JournalNeurochemical Research
Volume42
Early online date5 Aug 2017
DOIs
Publication statusPublished - Nov 2017

Keywords

  • d-Amino acid oxidase (DAO)
  • d-Serine
  • Enzyme occupancy
  • N-methyl-d-aspartate receptor (NMDAR)
  • Sodium benzoate

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