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

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756. Neurochem Res. 2017 Aug 05;: Authors: Howley E, Bestwick M, Fradley R, Harrison H, Leveridge M, Okada K, Fieldhouse C, Farnaby W, Canning H, Sykes AP, Merchant K, Hazel K, Kerr C, Kinsella N, Walsh L, Livermore DG, Hoffman I, Ellery J, Mitchell P, Patel T, Carlton M, Barnes M, Miller DJ 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; althoug...
Source: Neurochemical Research - Category: Neuroscience Authors: Tags: Neurochem Res Source Type: research