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.
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Niyada
authors.initials: N
authors.lastname: Hin
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Duvall
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Berry
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA.
authors.forename: Dana V
authors.initials: DV
authors.lastname: Ferraris
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: ttsukamoto@jhmi.edu.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D012694:Serine / Q000097:blood; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C000612709:5-hydroxy-1,2,4-triazin-6(1H)-one; D004791:Enzyme Inhibitors; D014227:Triazines; D012694:Serine; D003605:D-Amino-Acid Oxidase
keywords: Flavoenzyme; Pharmacokinetics; Schizophrenia; d-Amino acid oxidase; d-Serine