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

doi:10.1021/acs.jmedchem.5b00482

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 language	English (US)
Pages (from-to)	7258-7272
Number of pages	15
Journal	Journal of medicinal chemistry
Volume	58
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00482
State	Published - Sep 24 2015

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

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day = "24",

doi = "10.1021/acs.jmedchem.5b00482",

language = "English (US)",

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AU - Hin, Niyada

AU - Duvall, Bridget

AU - Ferraris, Dana

AU - Alt, Jesse

AU - Thomas, Ajit G.

AU - Rais, Rana

AU - Rojas, Camilo

AU - Wu, Ying

AU - Wozniak, Krystyna M.

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

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

Abstract

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