Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel
Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel
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DOI：
10.1124/mol.110.066928
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Denton, Jerod S.
中科院分区：
文献类型：
--
作者：
Bhave, Gautam;Chauder, Brian A.;Denton, Jerod S.
肾外髓钾（K+）通道，ROMK（Kir1.1），是一类新型袢利尿剂的假定药物靶点，可降低血容量和血压，而不会引起低钾血症。然而，缺乏选择性ROMK抑制剂阻碍了评估其治疗潜力的努力。在ROMK小分子调节剂的高通量筛选中，我们先前鉴定了一种有效且中等选择性的ROMK拮抗剂，7，13-双（4-硝基苄基）-1，4，10-三氧杂-7，13-二氮杂环十五烷（VU 590），其也抑制Kir7.1。由于ROMK和Kir7.1在肾单位中共表达，因此VU 590不是肾中ROMK功能的良好探针。在这里，我们描述了结构相关的抑制剂2，2 '-氧双（亚甲基）双（5-硝基-1H-苯并-[d]咪唑）（VU 591）的开发，其与VU 590一样有效，但对ROMK的选择性超过Kir7.1和超过65种其他潜在的脱靶点。VU 591似乎阻断了通道的细胞内孔。VU 591的开发可能使研究能够探索ROMK作为利尿靶点的可行性。
The renal outer medullary potassium (K+) channel, ROMK (Kir1.1), is a putative drug target for a novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack of selective ROMK inhibitors has hindered efforts to assess its therapeutic potential. In a high-throughput screen for small-molecule modulators of ROMK, we previously identified a potent and moderately selective ROMK antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (VU590), that also inhibits Kir7.1. Because ROMK and Kir7.1 are coexpressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of the structurally related inhibitor 2,2'-oxybis(methylene)bis(5-nitro-1H-benzo-[d]imidazole) (VU591), which is as potent as VU590 but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target.