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Assessment of the Target Engagement and d-Serine Biomarker Profiles of the d-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756

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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.

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Acknowledgements

The authors would like to gratefully thank Sarah Almond, Shyam Bechar, Richard Newman, Kamal Lalgi, Dhruval Patel, Stuart Stafford and John Robinson (Takeda Cambridge Ltd), Sean Gay (Takeda California,) and Ranjev Savopoulos (Assay Advantage Ltd). Whilst not contributing directly to the data presented within this paper each of those named above played important roles in identifying either the compounds synthesised or the methods by which to test them.

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Authors and Affiliations

  1. Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire, CB4 0PA, UK

    Eimear Howley, Michael Bestwick, Rosa Fradley, Helen Harrison, Mathew Leveridge, Charlotte Fieldhouse, Will Farnaby, Hannah Canning, Andy P. Sykes, Kevin Merchant, Katherine Hazel, Catrina Kerr, Natasha Kinsella, Louise Walsh, David G. Livermore, Jonathan Ellery, Phillip Mitchell, Toshal Patel, Mark Carlton, Matt Barnes & David J. Miller

  2. Biomolecular Research Laboratories, Shonan Research Center, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 25108555, Japan

    Kengo Okada

  3. Takeda California Inc., 10410 Science Center Dr, San Diego, CA, 92121, USA

    Isaac Hoffman

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  1. Eimear Howley
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  2. Michael Bestwick
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Correspondence to Rosa Fradley.

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Howley, E., Bestwick, M., Fradley, R. et al. Assessment of the Target Engagement and d-Serine Biomarker Profiles of the d-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756. Neurochem Res 42, 3279–3288 (2017). https://doi.org/10.1007/s11064-017-2367-9

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  • DOI: https://doi.org/10.1007/s11064-017-2367-9

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