6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel d -Amino Acid Oxidase Inhibitors

Niyada Hin, Bridget Duvall, Dana Ferraris, Jesse Alt, Ajit G. Thomas, Rana Rais, Camilo Rojas, Ying Wu, Krystyna M. Wozniak, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

Abstract

A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of d-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors, with IC50 values in the double-digit nanomolar range. The 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione pharmacophore appears metabolically resistant to O-glucuronidation unlike other structurally related DAAO inhibitors. Among them, 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11h was found to be selective over a number of targets and orally available in mice. Furthermore, oral coadministration of d-serine with 11h enhanced the plasma levels of d-serine in mice compared to the oral administration of d-serine alone, demonstrating its ability to serve as a pharmacoenhancer of d-serine.

Original languageEnglish (US)
Pages (from-to)7258-7272
Number of pages15
JournalJournal of medicinal chemistry
Volume58
Issue number18
DOIs
StatePublished - Sep 24 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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