Abstract
The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter’s syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5′-((1R,1′R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter’s syndrome type II features are manifested on exposure to ROMK inhibitors.
Footnotes
- Received May 17, 2016.
- Accepted July 14, 2016.
↵1 Current affiliation: Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana
↵2 Current affiliation: Consultant, General Biologicals Corp., Westfield, New Jersey
↵3 Current affiliation: Evotec, Princeton, New Jersey
↵4 Current affiliation: Bristol-Myers-Squibb, Princeton, New Jersey
↵5 Current affiliation: University of Texas-Rio Grande Valley, Edinburg, Texas
↵6 Current affiliation: Stemcentrx, South San Francisco, California
↵7 Current affiliation: Sanofi-Genzyme, Framingham, Massachusetts
↵8 Current affiliation: 3409 Park Place, Springfield, New Jersey
↵9 Current affiliation: Bayer HealthCare LLC, San Francisco, California
↵10 Current affiliation: Kanalis Consulting, L.L.C., Edison, New Jersey
C.H. and X.Z. contributed equally to this work.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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