ACS Medicinal Chemistry Letters
Letter
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In conclusion, we have discovered a class of selective small
molecule ROMK inhibitors starting from a high-throughput
screen of our internal sample collection. The program lead 5
was identified after isolation of a minor impurity from a
screening hit. Compound 5 was selective over other members
of the inward rectifier family of potassium channels but was
about 10-fold more potent on the hERG channel. Medicinal
chemistry efforts led to the identification of a number of
pharmacophores more suitable for drug development as
compared with the original nitrophenyl groups. Further SAR
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tool compound in animal models of diuresis and hypertension.
Future work will be centered in further enhancing the
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K. A.; Redha, R.; Fallen, K.; Lindsley, C. W.; Weaver, C. D.; Denton, J.
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the Renal Outer Medullary Potassium Channel and Kir7.1. Mol.
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(16) Bhave, G.; Chauder, B. A.; Liu, W.; Dawson, E. S.; Kadakia, R.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis of key compounds and the 86Rb+ assay protocol. This
material is available free of charge via the Internet at http://
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Vincent Tong for high-resolution mass
spectroscopy analysis of the key compounds.
■
(17) Solly, K.; Cassaday, J.; Felix, J. P.; Garcia, M. L.; Ferrer, M.;
Strulovici, B.; Kiss, L. Miniaturization and HTS of a FRET-based
membrane Potential Assay for K(ir) Channel Inhibitors. Assay Drug
Dev. Technol. 2008, 6 (2), 225−234.
(18) IC50 values were determined from 10-point concentration−
response curves where each point was run in triplicate.
(19) Assays were usually run at least twice, and the results were
generally within 20% of each other. Please see the Supporting
Information for the 86Rb+ efflux assay protocol.
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