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

Bence Szilágyi, Péter Kovács, G. Ferenczy, Anita Rácz, Krisztina Németh, J. Visy, P. Szabó, Janez Ilas, György T. Balogh, K. Monostory, István Vincze, T. Tábi, É. Szökő, György M. Keserű

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1579-1587
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number8
DOIs
Publication statusPublished - May 1 2018

Fingerprint

D-Amino-Acid Oxidase
Isatin
Derivatives
Serine
Calorimetry
Structure-Activity Relationship
N-Methyl-D-Aspartate Receptors
Titration
Assays
Brain
Schizophrenia
Chemical activation
Plasmas
Testing
Pharmaceutical Preparations

Keywords

  • Binding thermodynamics
  • D-Amino acid oxidase
  • Optimization
  • Protonation state

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Discovery of isatin and 1H-indazol-3-ol derivatives as D-amino acid oxidase (DAAO) inhibitors. / Szilágyi, Bence; Kovács, Péter; Ferenczy, G.; Rácz, Anita; Németh, Krisztina; Visy, J.; Szabó, P.; Ilas, Janez; Balogh, György T.; Monostory, K.; Vincze, István; Tábi, T.; Szökő, É.; Keserű, György M.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 8, 01.05.2018, p. 1579-1587.

Research output: Contribution to journalArticle

Szilágyi, Bence ; Kovács, Péter ; Ferenczy, G. ; Rácz, Anita ; Németh, Krisztina ; Visy, J. ; Szabó, P. ; Ilas, Janez ; Balogh, György T. ; Monostory, K. ; Vincze, István ; Tábi, T. ; Szökő, É. ; Keserű, György M. / Discovery of isatin and 1H-indazol-3-ol derivatives as D-amino acid oxidase (DAAO) inhibitors. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 8. pp. 1579-1587.
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