TY - JOUR T1 - Development of a selective small-molecule inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.066928 SP - mol.110.066928 AU - Gautam Bhave AU - Brian A. Chauder AU - Wen Liu AU - Eric S. Dawson AU - Rishin Kadakia AU - Thuy T. Nguyen AU - L. Michelle Lewis AU - Jens Meiler AU - C. David Weaver AU - Lisa M. Satlin AU - Craig W. Lindsley AU - Jerod S. Denton Y1 - 2010/10/06 UR - http://molpharm.aspetjournals.org/content/early/2010/10/06/mol.110.066928.abstract N2 - The renal outer medullary potassium channel, ROMK or 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, VU590, which also inhibits Kir7.1. Because ROMK and Kir7.1 are co-expressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of a structurally related inhibitor termed VU591 that is equally potent as VU590, but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 appears 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. ER -