Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate
Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate
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源自竞争性类胰蛋白酶抑制剂骨架的非竞争性凝血酶抑制剂的发现：分子识别的转变是由羧酸盐到膦酸盐的骨架转化引起的
DOI：
10.1016/j.bmcl.2015.06.039
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发表时间：
2015
影响因子：
2.7
通讯作者：
Tsutomu Yokomatsu
中科院分区：
文献类型：
--
作者：
Hiroshi Aoyama;Ryosuke Ijuin;Jun-ya Kato;Sarasa Urushiyama;Masashi Tetsuhashi;Yuichi Hashimoto;Tsutomu Yokomatsu
以我们先前开发的芳基羧酸型类胰蛋白酶选择性抑制剂1为基础，合成了一系列新型的末端和内部的磷酸酯类化合物。使用三种可用的丝氨酸蛋白酶，即胰蛋白酶、胰蛋白酶和凝血酶，在体外用酶抑制试验评估这些合成的化合物的效力。内膦酸衍生物6具有较强的凝血酶抑制活性，IC50值为1.0xμM，而在10μM时没有或仅表现出弱的胰酶和胰酶抑制作用。因此，羧酸盐的骨架转化为磷酸盐改变了凝血酶对这些抑制物的分子识别模式。
A novel series of terminal and internal phosphonate esters based on our previously developed aryl carboxylate-type tryptase selective inhibitor1was synthesized. The potency of these synthesized compounds was assessed in vitro with an enzyme inhibition assay using three available serine proteases, that is, tryptase, trypsin, and thrombin. The internal phosphonate derivative6showed potent thrombin inhibitory activity with an IC50value of 1.0 μM, whereas it exhibited no or only weak tryptase and trypsin inhibition at 10 μM. The Lineweaver–Burk plot analysis indicates that the inhibition pattern of thrombin with6is non-competitive in spite of the fact that the lead carboxylate compound1is competitive inhibitor. Therefore, the skeletal conversion of the carboxylate into a phosphonate alters the mode of molecular recognition of these inhibitors by thrombin.