D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold

Niyada Hin, Bridget Duvall, James F. Berry, Dana V. Ferraris, Rana Rais, Jesse Alt, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

Abstract

A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of d-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range. Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2-yl)methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance plasma d-serine levels following its co-administration with d-serine compared to the oral administration of d-serine alone.

Original languageEnglish (US)
Pages (from-to)2088-2091
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number8
DOIs
StatePublished - Apr 15 2016

Keywords

  • Flavoenzyme
  • Pharmacokinetics
  • Schizophrenia
  • d-Amino acid oxidase
  • d-Serine

ASJC Scopus subject areas

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

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