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

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.

SUBMITTER: Hin N 

PROVIDER: S-EPMC5003509 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Hin Niyada N   Duvall Bridget B   Ferraris Dana D   Alt Jesse J   Thomas Ajit G AG   Rais Rana R   Rojas Camilo C   Wu Ying Y   Wozniak Krystyna M KM   Slusher Barbara S BS   Tsukamoto Takashi T  

Journal of medicinal chemistry 20150903 18

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(2  ...[more]

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