TY - JOUR
T1 - 6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel d -Amino Acid Oxidase Inhibitors
AU - Hin, Niyada
AU - Duvall, Bridget
AU - Ferraris, Dana
AU - Alt, Jesse
AU - Thomas, Ajit G.
AU - Rais, Rana
AU - Rojas, Camilo
AU - Wu, Ying
AU - Wozniak, Krystyna M.
AU - Slusher, Barbara S.
AU - Tsukamoto, Takashi
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/9/24
Y1 - 2015/9/24
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.5b00482
DO - 10.1021/acs.jmedchem.5b00482
M3 - Article
C2 - 26309148
AN - SCOPUS:84942362195
SN - 0022-2623
VL - 58
SP - 7258
EP - 7272
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 18
ER -