Woo L W Lawrence, Bubert Christian, Sutcliffe Oliver B, Smith Andrew, Chander Surinder K, Mahon Mary F, Purohit Atul, Reed Michael J, Potter Barry V L
Medicinal Chemistry, Department of Pharmacy & Pharmacology and Sterix Limited, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
J Med Chem. 2007 Jul 26;50(15):3540-60. doi: 10.1021/jm061462b. Epub 2007 Jun 20.
By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.
通过将类固醇硫酸酯酶抑制药效团引入芳香化酶抑制剂1（YM511）中，生成了两个系列的单药双芳香化酶 - 硫酸酯酶抑制剂（DASI）。体外（JEG - 3细胞）表现最佳的DASI分别为5号（IC50（芳香化酶）= 0.82 nM；IC50（硫酸酯酶）= 39 nM）和14号（IC50（芳香化酶）= 0.77 nM；IC50（硫酸酯酶）= 590 nM）。本文展示了5号的X射线晶体学研究以及所选化合物在芳香化酶同源模型和类固醇硫酸酯酶晶体结构中的对接研究。单次口服10 mg/kg剂量后3小时，5号和14号在PMSG预处理的成年雌性Wistar大鼠中均能有效抑制芳香化酶和硫酸酯酶。对于5号，几乎观察到完全的双重抑制，但24小时后，抑制水平降至85%（芳香化酶）和72%（硫酸酯酶）。DASI 5不抑制醛固酮合成。一种强效且选择性的DASI的开发应能使评估双芳香化酶 - 硫酸酯酶抑制在激素依赖性乳腺癌中的治疗潜力成为可能。
