RT Journal Article
SR Electronic
T1 Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 42
OP 50
DO 10.1124/mol.110.066928
VO 79
IS 1
A1 Bhave, Gautam
A1 Chauder, Brian A.
A1 Liu, Wen
A1 Dawson, Eric S.
A1 Kadakia, Rishin
A1 Nguyen, Thuy T.
A1 Lewis, L. Michelle
A1 Meiler, Jens
A1 Weaver, C. David
A1 Satlin, Lisa M.
A1 Lindsley, Craig W.
A1 Denton, Jerod S.
YR 2011
UL http://molpharm.aspetjournals.org/content/79/1/42.abstract
AB 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.