6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.
6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.
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DOI：
10.1021/acs.jmedchem.5b00482
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发表时间：
2015-09-24
影响因子：
7.3
通讯作者：
Tsukamoto, Takashi
中科院分区：
文献类型：
--
作者：
Hin, Niyada;Duvall, Bridget;Ferraris, Dana;Alt, Jesse;Thomas, Ajit G.;Rais, Rana;Rojas, Camilo;Wu, Ying;Wozniak, Krystyna M.;Slusher, Barbara S.;Tsukamoto, Takashi
合成了一系列2-取代-6-羟基-1，2，4-三嗪-3，5（2 H，4 H）-二酮衍生物作为d-氨基酸氧化酶（DAAO）抑制剂。发现该系列中的许多化合物是有效的DAAO抑制剂，IC 50值在两位数纳摩尔范围内。与其他结构相关的DAAO抑制剂不同，6-羟基-1，2，4-三嗪-3，5（2 H，4 H）-二酮药效团似乎对O-葡萄糖醛酸化具有代谢抗性。其中6-羟基-2-（萘-1-基甲基）-1，2，4-三嗪-3，5（2 H，4 H）-二酮11 h被发现对许多靶点具有选择性并且在小鼠中口服有效。此外，与单独口服d-丝氨酸相比，口服d-丝氨酸与11 h联合给药增强了小鼠血浆中d-丝氨酸的水平，表明其能够作为d-丝氨酸的药物增强剂。
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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影响因子：
4.1
作者：
Maekawa, M;Okamura, T;Konno, R
通讯作者：
Konno, R
影响因子：
4
作者：
Terry-Lorenzo RT;Chun LE;Brown SP;Heffernan ML;Fang QK;Orsini MA;Pollegioni L;Hardy LW;Spear KL;Large TH
通讯作者：
Large TH
DOI：
10.1016/j.bbrc.2007.01.181
发表时间：
2007-04-06
影响因子：
3.1
作者：
Kawazoe, Tomoya;Tsuge, Hideaki;Fukui, Kiyoshi
通讯作者：
Fukui, Kiyoshi
影响因子：
6.7
作者：
Lange, Jos H. M.;Venhorst, Jennifer;Kruse, Chris G.
通讯作者：
Kruse, Chris G.
影响因子：
2.1
作者：
Branch, CL;Eggleston, DS;Tyler, JW
通讯作者：
Tyler, JW