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 Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)839-843
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number10
DOIs
StatePublished - Oct 11 2012

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Oxidoreductases
Amino Acids
Serine
Pharmacokinetics
Structure-Activity Relationship
Benzene
Swine
Plasmas

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase. / Berry, James F.; Ferraris, Dana V.; Duvall, Bridget; Hin, Niyada; Rais, Rana; Alt, Jesse; Thomas, Ajit G.; Rojas, Camilo; Hashimoto, Kenji; Slusher, Barbara; Tsukamoto, Takashi.

In: ACS Medicinal Chemistry Letters, Vol. 3, No. 10, 11.10.2012, p. 839-843.

Research output: Contribution to journalArticle

Berry, James F. ; Ferraris, Dana V. ; Duvall, Bridget ; Hin, Niyada ; Rais, Rana ; Alt, Jesse ; Thomas, Ajit G. ; Rojas, Camilo ; Hashimoto, Kenji ; Slusher, Barbara ; Tsukamoto, Takashi. / Synthesis and SAR of 1-hydroxy-1 H -benzo[ d ]imidazol-2(3 H)-ones as inhibitors of d -amino acid oxidase. In: ACS Medicinal Chemistry Letters. 2012 ; Vol. 3, No. 10. pp. 839-843.
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AU - Rais, Rana

AU - Alt, Jesse

AU - Thomas, Ajit G.

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