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.
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Niyada
authors: N
authors: Hin
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Bridget
authors: B
authors: Duvall
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Dana
authors: D
authors: Ferraris
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Jesse
authors: J
authors: Alt
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Ajit G
authors: AG
authors: Thomas
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Rana
authors: R
authors: Rais
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Camilo
authors: C
authors: Rojas
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Ying
authors: Y
authors: Wu
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Krystyna M
authors: KM
authors: Wozniak
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Barbara S
authors: BS
authors: Slusher
authors: Brain Science Institute, ‡Department of Neurology, and §Department of Molecular and Comparative Pathobiology, Johns Hopkins University , Baltimore, Maryland 21205, United States.
authors: Takashi
authors: T
authors: Tsukamoto
mesh_terms: D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D012694:Serine / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000603795:6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D012694:Serine; D003605:D-Amino-Acid Oxidase