Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: Drugs for cystic fibrosis and chronic bronchitis
Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: Drugs for cystic fibrosis and chronic bronchitis
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DOI：
10.1021/jm051134w
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发表时间：
2006-07-13
影响因子：
7.3
通讯作者：
Johnson, M. Ross
中科院分区：
文献类型：
--
作者：
Hirsh, Andrew J.;Molino, Bruce F.;Johnson, M. Ross
Amiloride(1)是一种典型的上皮钠通道（ENaC）阻滞剂，作为气雾剂用于改善遗传性疾病囊性纤维化患者的肺功能，但疗效有限。本研究旨在合成和鉴定更有效、不可逆的ENaC阻滞剂，靶向气溶胶治疗，具有最小的全身肾活性。合成了一系列新的2-取代酰基胍类似物，并评价了其对支气管ENaC的效价和可逆性。所有测试的化合物在阻断钠依赖性短路电流方面比阿米洛利更有效，可逆性更低。化合物30 ~ 34对ENaC的抑制作用最强，IC50值小于10 nM。在ENaC上发现了区域选择性的效价差异（化合物30、39和40），而没有立体特异性的效价差异（化合物33、34）。先导化合物32的效力是amiloride的102倍，可逆性比amiloride低5倍，并且显示出ENaC阻阻剂的最低IC50值。
Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent shortcircuit current than amiloride. Compounds 30-34 showed the greatest potency on ENaC with IC50 values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC50 value ever reported for an ENaC blocker.