Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: Alkenyl-amidines as new leads
Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: Alkenyl-amidines as new leads
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DOI：
10.1016/j.bmc.2008.10.058
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发表时间：
2008-12-15
影响因子：
3.5
通讯作者：
Clement, Bernd
中科院分区：
文献类型：
--
作者：
Kotthaus, Juerke;Schade, Dennis;Clement, Bernd
最近的研究表明，抑制二甲基精氨酸二甲氨基水解酶（DDAH）活性可能是一种通过提高n -omega-甲基化l -精氨酸（NMMA， ADMA）水平间接影响一氧化氮（NO）形成的新策略。这种方法是治疗与一氧化氮浓度增加相关疾病的一种替代策略。迄今为止，已知三类有效抑制剂：(1)五氟苯基磺酸盐（IC50 = 16-58 μ M, PaDDAH），也是精氨酸脱亚胺酶的抑制剂；(2)最有效的抑制剂是吲哚基硫代巴比妥酸（IC50 = 2-17 μ M, PaDDAH），通过虚拟模型确定；(3) l -精氨酸类似物，其最佳代表是N-omega-（2-甲氧基乙基）- l -精氨酸（IC50 = 22 μ M，大鼠DDAH）。基于这些已知结构，我们的目标是开发具有更高效价和对DDAH-1相对于NOS有更好选择性的人DDAH-1抑制剂。特别是，通过筛选不同取代的胍、脒和异硫脲来研究胍-片段的结合袋，以收集活性位点可能的结合模式信息。所有物质都通过平板阅读器格式和高效液相色谱法进行了测试，并确定了几种有效的抑制剂，其ki值从2到36 μ M不等，其中N-5-（1-亚氨基丁基-3-烯基）- l -鸟氨酸（L-VNIO）是迄今为止描述的最有效的人DDAH-1抑制剂。除了这些有效的抑制剂外，hDDAH-1的替代底物也被确定。(C) 2008 Elsevier Ltd版权所有。
Recent studies demonstrated that inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity could be a new strategy to indirectly affect nitric oxide ( NO) formation by elevating N-omega-methylated L-arginine ( NMMA, ADMA) levels. This approach is an alternate strategy for the treatment of diseases associated with increased NO-concentrations. To date, three classes of potent inhibitors are known: ( 1) pentafluorophenyl sulfonates (IC50 = 16-58 mu M, PaDDAH), which are also inhibitors for the arginine deiminase; ( 2) the most potent inhibitors are based on indolylthiobarbituric acid ( IC50 = 2-17 mu M, PaDDAH), which were identified by virtual modelling; and ( 3) L-arginine analogs, whose best representative is N-omega-(2-methoxyethyl)-L-arginine (IC50 = 22 mu M, rat DDAH). Based on these known structures, we aimed to develop inhibitors for the human DDAH-1 with improved potency and better relative selectivity for DDAH-1 over NOS. Particularly, the binding pocket of the guanidine-moiety was investigated by screening differently substituted guanidines, amidines and isothioureas in order to collect information on possible binding modes in the active site. All substances were tested in a plate-reader format and HPLC assay and several potent inhibitors were identified with Ki-values varying from 2 to 36 mu M, with N-5-(1-iminobut-3-enyl)-L-ornithine (L-VNIO) being the most potent inhibitor of the human DDAH-1 so far described. Besides these potent inhibitors alternate substrates for hDDAH-1 were identified as well. (C) 2008 Elsevier Ltd. All rights reserved.