Inhibitors of Renal Outer Medullary Potassium Channel

Title:	Inhibitors of Renal Outer Medullary Potassium Channel
Patent Application Number:	WO2016008064A1	Publication date:	January 21, 2016
Priority Application:	None	Priority date:	N/A
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:	Cardiovascular disease	Biological Target:	Renal outer medullary potassium channel (Kir1.1)
Summary:	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 −OC1–3alkyl;
	R2 is −H, =O, −OH, −C1–3alkyl or −OC1–3alkyl;
	R3a is −H, −C3–4cycloalkyl or −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 – C1–4alkyl optionally substituted with OH or 1–3 of −F;
	R5 is −H, halo, or −C1–3alkyl optionally substituted with −O–C1–3alkyl;
	R6 is −H or −C1–3alkyl;
	R7 is −H or −C1–3alkyl optionally substituted with −OH, −OCH3 or 1 to 3 of −F, or R7 is absent when n is zero;
Definitions: (continued)	R8 is −H or −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 =O, 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

The authors declare no competing financial interest.