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Bioorg Med Chem. 2018 May 1;26(8):1579-1587. doi: 10.1016/j.bmc.2018.02.004. Epub 2018 Feb 8.

Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid oxidase (DAAO) inhibitors.

Author information

1
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2. H-1117 Budapest, Hungary.
2
Chemical Biology Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2. H-1117 Budapest, Hungary.
3
MS Metabolomics Laboratory, Core Facility, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2. H-1117 Budapest, Hungary.
4
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
5
Compound Profiling Laboratory, Gedeon Richter plc. Gyömrői út 30-32, H-1103 Budapest, Hungary.
6
Metabolic Drug-Interactions Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2. H-1117 Budapest, Hungary.
7
Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, Budapest H-1089, Hungary.
8
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2. H-1117 Budapest, Hungary. Electronic address: gy.keseru@ttk.mta.hu.

Abstract

d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.

KEYWORDS:

Binding thermodynamics; Optimization; Protonation state; d-Amino acid oxidase

PMID:
29472125
DOI:
10.1016/j.bmc.2018.02.004
[Indexed for MEDLINE]

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