Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant 1R21-NS57041-1]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants 1R01-DK082884, DK038470, P30-DK079307]; the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM080403, T32-GM07628]; the National Institutes of Health National Institute of Mental Health [Grants U54MH074427, 1U54-MH084659]; the American Heart Association Southeast Affiliate [Beginning Grant-in-Aid 0865106E]; and the National Kidney Foundation [Postdoctoral Fellowhip].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.066928.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.-
ABBREVIATIONS:
- ROMK
- renal outer medullary potassium (K+) channel
- TAL
- thick ascending limb
- hERG
- human ether-à-go-go-related gene
- HEK
- human embryonic kidney
- cRNA
- 7-methyl guanosine-capped RNA
- BNBI
- 1,3-bis(5-nitro-1H-benzo[d]imidazol-2-yl)propane
- DMSO
- dimethyl sulfoxide
- CD
- collecting duct
- Kir
- inward rectifying potassium
- BK
- large conductance K+ channels
- TPNQ
- tertiapin-Q
- ABS
- antenatal Bartter syndrome
- VU590
- 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane
- VU591
- 2,2′-oxybis(methylene)bis(5-nitro-1H-benzo[d]imidazole.
- Received June 14, 2010.
- Accepted October 6, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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