PMID- 28780732
OWN - NLM
STAT- MEDLINE
DCOM- 20180626
LR  - 20181113
IS  - 1573-6903 (Electronic)
IS  - 0364-3190 (Linking)
VI  - 42
IP  - 11
DP  - 2017 Nov
TI  - Assessment of the Target Engagement and D-Serine Biomarker Profiles of the 
      D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.
PG  - 3279-3288
LID - 10.1007/s11064-017-2367-9 [doi]
AB  - 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.
FAU - Howley, Eimear
AU  - Howley E
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Bestwick, Michael
AU  - Bestwick M
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Fradley, Rosa
AU  - Fradley R
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK. rosa_fradley@hotmail.co.uk.
FAU - Harrison, Helen
AU  - Harrison H
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Leveridge, Mathew
AU  - Leveridge M
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Okada, Kengo
AU  - Okada K
AD  - Biomolecular Research Laboratories, Shonan Research Center, Takeda Pharmaceutical 
      Company Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 25108555, Japan.
FAU - Fieldhouse, Charlotte
AU  - Fieldhouse C
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Farnaby, Will
AU  - Farnaby W
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Canning, Hannah
AU  - Canning H
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Sykes, Andy P
AU  - Sykes AP
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Merchant, Kevin
AU  - Merchant K
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Hazel, Katherine
AU  - Hazel K
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Kerr, Catrina
AU  - Kerr C
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Kinsella, Natasha
AU  - Kinsella N
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Walsh, Louise
AU  - Walsh L
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Livermore, David G
AU  - Livermore DG
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Hoffman, Isaac
AU  - Hoffman I
AD  - Takeda California Inc., 10410 Science Center Dr, San Diego, CA, 92121, USA.
FAU - Ellery, Jonathan
AU  - Ellery J
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Mitchell, Phillip
AU  - Mitchell P
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Patel, Toshal
AU  - Patel T
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Carlton, Mark
AU  - Carlton M
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Barnes, Matt
AU  - Barnes M
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
FAU - Miller, David J
AU  - Miller DJ
AD  - Takeda Cambridge Ltd, 418 Cambridge Science Park, Milton Road, Cambridge, 
      Cambridgeshire, CB4 0PA, UK.
LA  - eng
PT  - Journal Article
DEP - 20170805
PL  - United States
TA  - Neurochem Res
JT  - Neurochemical research
JID - 7613461
RN  - 0 (6-((4-chlorophenyl)methyl)-4-hydroxy-2,3-dihydropyridazin-3-one)
RN  - 0 (Biomarkers)
RN  - 0 (Chlorobenzenes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyridazines)
RN  - 452VLY9402 (Serine)
RN  - EC 1.4.3.- (DAO protein, human)
RN  - EC 1.4.3.3 (D-Amino-Acid Oxidase)
RN  - OJ245FE5EU (Sodium Benzoate)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Cerebellum/*metabolism
MH  - Chlorobenzenes/administration & dosage/chemistry/*pharmacology
MH  - Crystallography, X-Ray
MH  - D-Amino-Acid Oxidase/*antagonists & inhibitors/*metabolism
MH  - Enzyme Inhibitors/administration & dosage/chemistry/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pyridazines/administration & dosage/chemistry/*pharmacology
MH  - Serine/*metabolism
MH  - Sodium Benzoate/administration & dosage/chemistry/*pharmacology
OTO - NOTNLM
OT  - D-Amino acid oxidase (DAO)
OT  - D-Serine
OT  - Enzyme occupancy
OT  - N-methyl-D-aspartate receptor (NMDAR)
OT  - Sodium benzoate
EDAT- 2017/08/07 06:00
MHDA- 2018/06/27 06:00
CRDT- 2017/08/07 06:00
PHST- 2017/05/02 00:00 [received]
PHST- 2017/07/24 00:00 [accepted]
PHST- 2017/07/20 00:00 [revised]
PHST- 2017/08/07 06:00 [pubmed]
PHST- 2018/06/27 06:00 [medline]
PHST- 2017/08/07 06:00 [entrez]
AID - 10.1007/s11064-017-2367-9 [pii]
AID - 10.1007/s11064-017-2367-9 [doi]
PST - ppublish
SO  - Neurochem Res. 2017 Nov;42(11):3279-3288. doi: 10.1007/s11064-017-2367-9. Epub 
      2017 Aug 5.