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

Title Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.
Authors E. Howley; M. Bestwick; R. Fradley; H. Harrison; M. Leveridge; K. Okada; C. Fieldhouse; W. Farnaby; H. Canning; A.P. Sykes; K. Merchant; K. Hazel; C. Kerr; N. Kinsella; L. Walsh; D.G. Livermore; I. Hoffman; J. Ellery; P. Mitchell; T. Patel; M. Carlton; M. Barnes; D.J. Miller
Journal Neurochem Res
DOI 10.1007/s11064-017-2367-9
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.

Citation E. Howley; M. Bestwick; R. Fradley; H. Harrison; M. Leveridge; K. Okada; C. Fieldhouse; W. Farnaby; H. Canning; A.P. Sykes; K. Merchant; K. Hazel; C. Kerr; N. Kinsella; L. Walsh; D.G. Livermore; I. Hoffman; J. Ellery; P. Mitchell; T. Patel; M. Carlton; M. Barnes; D.J. Miller.Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.. Neurochem Res. 2017;42(11):32793288. doi:10.1007/s11064-017-2367-9

Related Elements

Sodium

Sodium Bohr ModelSee more Sodium products. Sodium (atomic symbol: Na, atomic number: 11) is a Block D, Group 5, Period 4 element with an atomic weight of 22.989769. The number of electrons in each of Sodium's shells is [2, 8, 1] and its electron configuration is [Ne] 3s1. The sodium atom has a radius of 185.8 pm and a Van der Waals radius of 227 pm. Sodium was discovered and first isolated by Sir Humphrey Davy in 1807. In its elemental form, sodium has a silvery-white metallic appearance. It is the sixth most abundant element, making up 2.6 % of the earth's crust. Sodium does not occur in nature as a free element and must be extracted from its compounds (e.g., feldspars, sodalite, and rock salt). The name Sodium is thought to come from the Arabic word suda, meaning "headache" (due to sodium carbonate's headache-alleviating properties), and its elemental symbol Na comes from natrium, its Latin name.

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