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

doi:10.1016/j.bmcl.2016.02.068

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

School of Medicine

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

8 Scopus citations

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 language	English (US)
Pages (from-to)	2088-2091
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2016.02.068
State	Published - 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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10.1016/j.bmcl.2016.02.068

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@article{149aa98bd87c4bbab268d3faa8825988,

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

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.",

keywords = "Flavoenzyme, Pharmacokinetics, Schizophrenia, d-Amino acid oxidase, d-Serine",

author = "Niyada Hin and Bridget Duvall and Berry, {James F.} and Ferraris, {Dana V.} and Rana Rais and Jesse Alt and Camilo Rojas and Slusher, {Barbara S.} and Takashi Tsukamoto",

note = "Funding Information: This work was in part supported by the National Institutes of Health ( R01MH091387 to T.T.) and the Johns Hopkins Brain Science Institute . Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd.",

year = "2016",

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doi = "10.1016/j.bmcl.2016.02.068",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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AU - Hin, Niyada

AU - Duvall, Bridget

AU - Berry, James F.

AU - Ferraris, Dana V.

AU - Rais, Rana

AU - Alt, Jesse

AU - Rojas, Camilo

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

N1 - Funding Information: This work was in part supported by the National Institutes of Health ( R01MH091387 to T.T.) and the Johns Hopkins Brain Science Institute . Publisher Copyright: © 2016 Elsevier Ltd.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - 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.

AB - 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.

KW - Flavoenzyme

KW - Pharmacokinetics

KW - Schizophrenia

KW - d-Amino acid oxidase

KW - d-Serine

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

Abstract

Keywords

ASJC Scopus subject areas

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