PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett

Inhibitors of Renal Outer Medullary Potassium Channel Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States Title:

Inhibitors of Renal Outer Medullary Potassium Channel

Patent Application Number: WO2016008064A1

Publication date:

January 21, 2016

Priority date:

N/A

Priority Application:

None

Inventors:

Suzuki, T.; Vacca, J. P.; Pu, Z.; Xu, S.; Pasternak, A.; Davies, I.; Ding, F. X.; Jiang, J.

Assignee Company:

Merck Sharp and Dohme Co.

Disease Area: Summary:

Cardiovascular disease Biological Target: Renal outer medullary potassium channel (Kir1.1) A number of critically important biological systems depend on the proper regulation of movement of potassium ions across biological membranes. One class of potassium channels, the voltage gated potassium channels, open and close in response to changes in transmembrane potential. To date, 78 isoforms have been identified, and they can be grouped as either inwardly rectifying or outwardly rectifying channels. The renal outer medullary potassium channel, also referred to as Kir1.1, is a member of the inwardly rectifying subfamily and plays a prominent role in kidney function. This channel is part of the potassium recycling system in the luminal membrane that ensures proper function of the Na+/K+/2Cl cotransporter in the ascending loop of Henle (TALH). It is also expressed in the cortical collecting duct of the kidney, where it helps to regulate potassium secretion, and its action is tightly coupled to sodium uptake. It has been hypothesized that selective Kir1.1 blockade would result in diuretic activity that would have a positive impact on cardiovascular diseases such as hypertension and heart failure. It has been further suggested that blockade of this channel would lower blood pressure without causing hypokalemia, a potential side effect of conventional diuretics. The present application discloses a series of compounds that selectively block Kir1.1 function and are potentially useful for the treatment of cardiovascular diseases such as hypertension, heart failure and chronic kidney disease, and conditions associated with excessive salt and water retention.

Important Compound Classes:

Definitions:

Z is

X is C(R4) or N; Rl is

H, halo,

OH, or

R2 is

H, dO,

OH,

R3a is

H,

OC1 3alkyl; C1 3alkyl or

C3 4cycloalkyl or

OC1 3alkyl;

C1 3alkyl optionally substituted with

OCH3 or 1 to 3 of

F;

R3b is H or C1 3alkyl, or R3b is absent when the dashed bond is a double bond; or R3a and R3b are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl; R4 is H, halo, CN, C3 6cycloalkyl, C(O)OC1 4alkyl, OC1 4alkyl, or 1 3 of

C1 4alkyl optionally substituted with OH or

F;

R5 is

H, halo, or

R6 is

H or

C1 3alkyl;

R7 is

H or

C1 3alkyl optionally substituted with

C1 3alkyl optionally substituted with OH,

O C1 3alkyl; OCH3 or 1 to 3 of

F, or R7 is absent when n is zero;

Received: March 27, 2016 Published: April 22, 2016 r 2016 American Chemical Society

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dx.doi.org/10.1021/acsmedchemlett.6b00131 | ACS Med. Chem. Lett. 2016, 7, 447–448

ACS Medicinal Chemistry Letters Definitions: (continued)

R8 is

H or

PATENT HIGHLIGHT C1 3alkyl, or R8 is absent when n is zero; or R7 and R8 are joined together with the carbon to which they are both

attached to form cyclopropyl or cyclobutyl; R9 is

H, halo,

OH,

C1 3alkyl,

OC1 3alkyl or

CH2OH;

R10 is H, or C1 3alkyl optionally substituted with OH, OCH3, or 1 to 3 of F; R11 is H, or C1 3alkyl optionally substituted with OH, OCH3, or 1 to 3 of F; or R10 and R11 are joined together to represent CH2 CH2 ,

CH2 N(CH3) CH2 , or

CH2OCH2 ;

R12 and R13 are each independently H, halo, CN, C3 6cycloalkyl, C(O)OC1 4alkyl, OC1 4alkyl, or C1 4alkyl optionally substituted with OH or 1 3 of F; m is zero where R3b is absent, or one where R3b is present; the partially dashed double bond represents a single or double bond wherein: (i) when m is one, then the dashed bond is a single bond; and (ii) when m is zero and R2 is not dO, then the dashed bond is a double bond; and n IS zero or one. Key Structures:

Recent Review Articles:

1. Martelli, A.; Testai, L.; Breschi, M. C.; Calderone, V. Inhibitors of the renal outer medullary potassium channel: A patent review. Expert Opin. Ther. Patents; 2015, 25 (9), 1035 1051. 2. Garcia, M. L.; Kaczorowski, G. J. Targeting the inward-rectifier potassium channel ROMK in cardiovascular disease. Curr. Opin. Pharmacol.; 2014, 15, 1 6.

Biological Assay:

Kir1.1 Thallium flux assay

Biological Data:

Claims:

16 total claims 13 composition of matter claims 3 method of use claims

’ AUTHOR INFORMATION Corresponding Author

*Tel: 215-707-1085. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

448

dx.doi.org/10.1021/acsmedchemlett.6b00131 |ACS Med. Chem. Lett. 2016, 7, 447–448