The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartters Syndrome Type II Phenotype

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.

Effect of diuretics on renal tubular transport of calcium and magnesium

“…However, a single dose elicited an initial increase in urinary Ca 2ϩ and Mg 2ϩ excretion when measured initially or after 7 days of treatment, paralleling the loss of Cl Ϫ (103). In spontaneously hypertensive rats, urinary Ca 2ϩ dose dependently increased after ROMK inhibitor administration for 4 days (103). Furthermore, high-dose ROMK inhibition increased urinary excretion of Ca 2ϩ in Dahl salt-sensitive rats on a high-NaCl diet.…”

“…Therefore, blocking the ROMK channel would allow inhibition of both Na ϩ and K ϩ transport in the TAL, along with substantial inhibition of K ϩ secretion in more distal parts, potentially minimizing urinary K ϩ losses. In fact, pharmacological inhibition of ROMK leads to significant natriuresis and diuresis, effectively lowering blood pressure, without substantial effects on urinary K ϩ excretion (103). Administration of ROMK inhibitors to dogs for 7 days did not alter serum levels of either Ca 2ϩ or Mg 2ϩ (103).…”

“…In fact, pharmacological inhibition of ROMK leads to significant natriuresis and diuresis, effectively lowering blood pressure, without substantial effects on urinary K ϩ excretion (103). Administration of ROMK inhibitors to dogs for 7 days did not alter serum levels of either Ca 2ϩ or Mg 2ϩ (103). However, a single dose elicited an initial increase in urinary Ca 2ϩ and Mg 2ϩ excretion when measured initially or after 7 days of treatment, paralleling the loss of Cl Ϫ (103).…”

Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics

“…27 was also selective toward other members of the Kir family (Kir2.3, Kir2.1, Kir4.1, Kir2.3 Kir7.1; IC 50 > 30 μM) and showed good selectivity toward other cardiac ion channels (Cav1.0, Nav1.5; IC 50 > 30 μM). In summary 27 , renamed as MK-7145, demonstrated improved hERG selectivity, dose dependent lowering of blood pressure and was selected as the first small molecule ROMK inhibitor to enter clinical development . MK-7145 entered into three separate clinical trials looking at effects on blood pressure in male patients with hypertension (NCT01370655), pharmacokinetics following single dose in patients with moderate renal insufficiency (NCT01832103), and safety and tolerability study in patients with renal insufficiency and heart failure with renal insufficiency (NCT01558674) .…”

“…In summary 27, renamed as MK-7145, demonstrated improved hERG selectivity, dose dependent lowering of blood pressure and was selected as the first small molecule ROMK inhibitor to enter clinical development. 35 MK-7145 entered into three separate clinical trials looking at effects on blood pressure in male patients with hypertension (NCT01370655), pharmacokinetics following single dose in patients with moderate renal insufficiency (NCT01832103), and safety and tolerability study in patients with renal insufficiency and heart failure with renal insufficiency (NCT01558674). 36 Unfortunately, second and third trials have been withdrawn and terminated, respectively.…”