Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase

James F. Berry; Dana V. Ferraris; Bridget Duvall; Niyada Hin; Rana Rais; Jesse Alt; Ajit G. Thomas; Camilo Rojas; Kenji Hashimoto; Barbara S. Slusher; Takashi Tsukamoto

doi:10.1021/ml300212a

Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase

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

School of Medicine

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

24 Scopus citations

Abstract

A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of d-amino acid oxidase (DAAO). The inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC ₅₀ values of the compounds ranging from 70 nM to greater than 100 μM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Two of these compounds were given to mice orally together with d-serine to assess their effects on plasma d-serine pharmacokinetics.

Original language	English (US)
Pages (from-to)	839-843
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	10
DOIs	https://doi.org/10.1021/ml300212a
State	Published - Oct 11 2012

Keywords

D-amino acid oxidase (DAAO)
D-serine
NMDA receptors
glucuronidation

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml300212a

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title = "Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase",

abstract = "A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of d-amino acid oxidase (DAAO). The inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC 50 values of the compounds ranging from 70 nM to greater than 100 μM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Two of these compounds were given to mice orally together with d-serine to assess their effects on plasma d-serine pharmacokinetics.",

keywords = "D-amino acid oxidase (DAAO), D-serine, NMDA receptors, glucuronidation",

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

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journal = "ACS Medicinal Chemistry Letters",

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AU - Berry, James F.

AU - Ferraris, Dana V.

AU - Duvall, Bridget

AU - Hin, Niyada

AU - Rais, Rana

AU - Alt, Jesse

AU - Thomas, Ajit G.

AU - Rojas, Camilo

AU - Hashimoto, Kenji

AU - Slusher, Barbara S.

AU - Tsukamoto, Takashi

PY - 2012/10/11

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AB - A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of d-amino acid oxidase (DAAO). The inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC 50 values of the compounds ranging from 70 nM to greater than 100 μM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Two of these compounds were given to mice orally together with d-serine to assess their effects on plasma d-serine pharmacokinetics.

KW - D-amino acid oxidase (DAAO)

KW - D-serine

KW - NMDA receptors

KW - glucuronidation

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Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase

Abstract

Keywords

ASJC Scopus subject areas

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