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Potential of Renal Outer Medullary Potassium (ROMK) Channel as Treatments for Hypertension and Heart Failure Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Inhibitors of The Renal Outer Medullary Potassium Channel
Patent Application Number:
US 2016/0304515 A1
Publication date:
October 20, 2016
Priority Application:
US 61/917,564
Priority date:
December 18, 2013
Inventors:
Chobanian, H.; Pio, B.; Guo, Y.; Ding, F.-X.; Dong, S.; Walsh, S.P.; Jiang, J.; Kim, D.
Assignee Company:
Merck Sharp & Dohme Corp., Rahway, NJ, USA
Disease Area:
Hypertension and heart failure
Summary:
The invention in this patent application relates to compounds represented generally by Formula (I), which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (also known as Kir1.1) channel. These compounds may potentially be useful as diuretic and/or natriuretic agents that can treat cardiovascular diseases such as hypertension, heart failure, chronic kidney disease, and other conditions associated with excessive salt and water retention. The ROMK channel is a member of the inward rectifier family of potassium channels. It is expressed in two regions of the kidney. The first is the thick ascending loop of Henle (TALH), where it participates in K+ recycling across the luminal membrane. This is a critical process for the function of Na+/K+/2Cl− cotransporter, which is the rate-determining step for salt reuptake in this part of the nephron. The second is the cortical collecting duct (CCD) where it plays an important role in K+ secretion, which is coupled to sodium uptake through the amiloride-sensitive sodium channel. Recent studies have suggested that inhibitors of ROMK could potentially act as potent diuretics through the inhibiting Na+ reabsorption in the TALH and minimizing urinary K+ loss in the CCD. Therefore, selective inhibition of ROMK is a promising potential therapeutic target that may lead to the development of a new treatments for hypertension. Selective ROMK inhibitors may act as advantageous class of loop diuretics that can lower blood pressure without the known adverse effects of the currently used diuretics such as hypokalemia (low potassium) or hyperkalemia (high potassium), new onset of diabetes, and dyslipidemia. The inventors referred to the known selective ROMK inhibitor VU591 that showed promising results as it seems to block the intracellular pore of the ROMK channel.
Biological Target:
The Renal Outer Medullary Potassium (ROMK) channel (Kir1.1)
They also referred to several previous patent applications from Merck that described different ROMK inhibitors. However, in spite of the number of known inhibitors, there is still a need to discover novel selective small molecule inhibitors of ROMK channel such as the compounds of Formula (I). These compounds could potentially be used for the treatment of hypertension, heart failure, and other conditions where treatment with a diuretic or natriuretic would be beneficial.
Important Compound Classes:
Formula (I)
Received: November 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.6b00457 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Key Structures:
The inventors described the structures and the synthesis procedures for 47 examples of Formula (I) compounds including the following representative examples:
Biological Assay:
Thallium Flux Assay
Biological Data:
The biological data obtained from testing the above representative examples are listed in the following table. The majority of the compounds of Formula (I) were tested using the Thallium Flux Assay; however, some examples were tested using 86Rb+ Efflux Assay and are marked with (Rb).
Recent Review Articles:
1. Martelli, A.; Testai, L.; Breschi, Maria, C.; Calderone, V. Expert Opin. Ther. Pat. 2015, 25 (9), 1035−1051. 2. Wang, T. Clin. Exp. Nephrol. 2012, 16 (1), 49−54. 3. Bhave, G.; Chauder, B. A.; Liu, W.; Dawson, E. S.; Kadakia, R.; Nguyen, T. T.; Lewis, L. M.; Meiler, J.; Weaver, C. D.; Satlin, L. M.; Lindsley, C. W.; Denton, J. S. Mol. Pharmacol. 2011, 79 (1), 42−50. 4. Welling, P. A.; Ho, K. Am. J. Physiol.-Renal Physiol. 2009, 297 (4), F849−63.
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AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
B
DOI: 10.1021/acsmedchemlett.6b00457 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
