A letrozole-based dual aromatase–sulphatase inhibitor with in vivo activity
A letrozole-based dual aromatase–sulphatase inhibitor with in vivo activity
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具有体内活性的基于来曲唑的双重芳香酶-硫酸酯酶抑制剂
DOI：
10.1016/j.jsbmb.2004.12.028
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
B. Potter
中科院分区：
文献类型：
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作者：
P. Wood;L. Woo;A. Humphreys;S. Chander;A. Purohit;M. Reed;B. Potter
芳香酶抑制剂在治疗激素依赖性乳腺癌中的作用已得到充分证实。然而，现在人们认识到类固醇硫酸酯酶（STS）抑制剂代表了一种新形式的内分泌治疗。为了探索单药双重抑制的潜在优势，我们最近在芳香酶抑制剂YM511的基础上开发了一系列芳香酶-硫酸酯酶双重抑制剂（DASI）。我们在这里报告了一种新的 DASI 结构类别，通过将用于 STS 抑制的药效团（即苯酚氨基磺酸酯）引入另一种已建立的芳香酶抑制剂来曲唑中而获得。因此，合成了双氨基磺酸盐9，其在JEG-3细胞中对芳香酶的IC50值为3044nM，对STS的IC50值>10μM。然而，单次口服剂量10mg/kg时，9在给药24小时后，对芳香酶和大鼠肝脏STS的抑制作用分别为60%和88%。合成了 9 的拟议代谢物，甲醇 10。尽管在 JEG-3 细胞中也显示出较弱的 STS 抑制作用，但单次口服剂量 10mg/kg 时，10 对大鼠肝脏 STS 活性的抑制程度与 9 相同。因此，基于来曲唑的 DASI 概念已经得到验证，并且可以进一步开发和修改以用于治疗开发。
The role of aromatase inhibitors in the treatment of hormone-dependent breast cancer is well established. However, it is now recognised that steroid sulphatase (STS) inhibitors represent a new form of endocrine therapy. To explore the potential advantage of dual inhibition by a single agent, we recently developed a series of dual aromatase–sulphatase inhibitors (DASIs) based on the aromatase inhibitor YM511. We report here a new structural class of DASI obtained by obtained introducing the pharmacophore for STS inhibition, i.e. a phenol sulphamate ester into another established aromatase inhibitor letrozole. Hence, the bis-sulphamate 9 was synthesised which exhibited IC50values of 3044nM for aromatase and >10μM for STS in JEG-3 cells. However, at a single oral dose of 10mg/kg, 9 inhibited aromatase and rat liver STS by 60% and 88%, respectively, 24h after administration. A proposed metabolite of 9, carbinol 10, was synthesised. Despite also showing weak STS inhibition in JEG-3 cells, 10 inhibited rat liver STS activity to the same extent as 9 at a single oral dose of 10mg/kg. Thus, the concept of a letrozole-based DASI has been validated and could be further developed and modified for therapeutic exploitation.