A leukotriene C4 synthase inhibitor with the backbone of 5-(5-methylene-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid
A leukotriene C4 synthase inhibitor with the backbone of 5-(5-methylene-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid
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DOI：
10.1093/jb/mvt007
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发表时间：
2013-05-01
影响因子：
2.7
通讯作者：
Miyano, Masashi
中科院分区：
文献类型：
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作者：
Ago, Hideo;Okimoto, Noriaki;Miyano, Masashi
半胱氨酰白三烯（cys-LTs）、白三烯C-4（LTC 4）及其代谢产物LTD 4和LTE 4是哮喘和其他炎性疾病中的促炎性脂质介质。它们通过5-脂氧合酶/LTC 4合酶（LTC 4S）途径产生，并通过至少两种不同的G蛋白偶联受体起作用。抑制人LTC 4S将为治疗cys-LT相关的炎症性疾病提供一条简单的途径。在这里，我们在酶测定和全细胞测定中显示具有5-（5-亚甲基-4-氧代-4，5-二氢噻唑-2-基氨基）烟酸部分的化合物抑制LTC 4合成，谷胱甘肽与前体LTA（4）缀合。对600万种化合物的分级计算机筛选提供了300，000个数据集用于对接，并且在基于LTC 4S的晶体结构的能量最小化之后，选择111种化合物作为谷胱甘肽竞争性抑制剂的候选物。这些化合物中的一种显示出显著的抑制活性，随后发现其衍生物5-（（Z）-5-（（E）-2-甲基-3-苯基亚丙基）-4-氧代-4，5-二氢噻唑-2-基氨基）戊酸（化合物1）是最有效的抑制剂。酶测定显示IC 50为1.9 μ M，相应的95%置信区间为1.7 - 2.2 μ M。全细胞测定显示化合物1是细胞可渗透的并且以浓度依赖性方式抑制LTC 4合成。
The cysteinyl leukotrienes (cys-LTs), leukotriene C-4 (LTC4) and its metabolites, LTD4 and LTE4, are proinflammatory lipid mediators in asthma and other inflammatory diseases. They are generated through the 5-lipoxygenase/LTC4 synthase (LTC4S) pathway and act via at least two distinct G protein-coupled receptors. The inhibition of human LTC4S will make a simple way to treat the cys-LT relevant inflammatory diseases. Here, we show that compounds having 5-(5-methylene-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid moiety suppress LTC4 synthesis, glutathione conjugation to the precursor LTA(4), in both an enzyme assay and a whole-cell assay. Hierarchical in silico screenings of 6 million compounds provided 300,000 dataset for docking, and after energy minimization based on the crystal structure of LTC4S, 111 compounds were selected as candidates for a competitive inhibitor to glutathione. One of those compounds showed significant inhibitory activity, and subsequently, its derivative 5-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-4,5-dihydrothiazol-2-ylamino) isophthalic acid (compound 1) was found to be the most potent inhibitor. The enzyme assay showed the IC50 was 1.9 mu M and the corresponding 95% confidence interval was from 1.7 to 2.2 mu M. The whole-cell assay showed that compound 1 was cell permeable and inhibited LTC4 synthesis in a concentration dependent manner.