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Abstract：
The K+-sparing diuretic amiloride elicits anticancer activities in multiple animal models. During our recent medicinal chemistry campaign aiming to identify amiloride analogs with improved properties for potential use in cancer, we discovered novel 6-(hetero)aryl-substituted amiloride and 5-(N,N-hexamethylene)amiloride (HMA) analogs with up to 100-fold higher potencies than the parent compounds against urokinase plasminogen activator (uPA), one of amiloride\'s putative anticancer targets, and no diuretic or antikaliuretic effects. Here, we report the systematic evaluation of structure-property relationships (lipophilicity, aqueous solubility and in vitro metabolic stability in human and mouse liver microsomes) in twelve matched pair analogs selected from our 6-substituted amiloride and HMA libraries. Mouse plasma stability, plasma protein binding, Caco-2 cell permeability, cardiac ion channel activity and pharmacokinetics in mice (PO and IV) and rats (IV) are described alongside amiloride and HMA comparators for a subset of the four most promising matched-pair analogs. The findings combined with earlier uPA activity/selectivity and other data ultimately drove selection of two analogs (AA1-39 and AA1-41) that showed efficacy in separate mouse cancer metastasis studies.
摘要：
保留钾的利尿剂阿米洛利在多种动物模型中引起抗癌活性。在我们最近的药物化学运动旨在确定阿米洛利类似物具有改善的性质，用于癌症的潜在用途，我们发现了新的6-（杂）芳基取代的阿米洛利和5-（N，N-六亚甲基）阿米洛利（HMA）类似物对尿激酶纤溶酶原激活剂（uPA）的效力比母体化合物高100倍，阿米洛利推定的抗癌靶点之一，没有利尿或抗利尿作用。这里,我们报告了结构-性质关系的系统评估(亲脂性，从我们的6取代阿米洛利和HMA文库中选择的12对匹配的类似物中，在人和小鼠肝微粒体中的水溶性和体外代谢稳定性）。小鼠血浆稳定性,血浆蛋白结合，Caco-2细胞通透性，与阿米洛利和HMA比较剂一起描述了小鼠（PO和IV）和大鼠（IV）中的心脏离子通道活性和药代动力学四种最有前途的配对类似物的子集。与早期uPA活性/选择性和其他数据相结合的发现最终驱动了在单独的小鼠癌症转移研究中显示功效的两种类似物(AA1-39和AA1-41)的选择。
