TY - JOUR
T1 - Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel
AU - Bhave, Gautam
AU - Chauder, Brian A.
AU - Liu, Wen
AU - Dawson, Eric S.
AU - Kadakia, Rishin
AU - Nguyen, Thuy T.
AU - Lewis, L. Michelle
AU - Meiler, Jens
AU - Weaver, C. David
AU - Satlin, Lisa M.
AU - Lindsley, Craig W.
AU - Denton, Jerod S.
PY - 2011/1
Y1 - 2011/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=78651340650&partnerID=8YFLogxK
U2 - 10.1124/mol.110.066928
DO - 10.1124/mol.110.066928
M3 - Article
C2 - 20926757
AN - SCOPUS:78651340650
SN - 0026-895X
VL - 79
SP - 42
EP - 50
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 1
ER -