Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure

Abstract

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

Emerging Targets of Diuretic Therapy

“…The phenotypes of several double knockout mice suggest the potential outcomes of combination diuretic therapy. Recent advances in the understandings of renal salt handling have laid strong foundations for future promising novel diuretics to achieve this goal ( Table ) . Finally, agents that promote water diuresis with minimal saluretic effect, such as UT‐A inhibitors, would be particularly beneficial for conditions associated with hyponatremia and refractory edema.…”

“…To further improve the specificity toward ROMK, the same group developed MK‐7145, which showed superior diuretic and natriuretic effects (∼8‐fold increase vs. vehicle) compared to thiazide (∼5‐fold) and lowered systolic blood pressure by 20 mmHg at a dose of 10 mg/kg/day with no reported cardiac side effects. The kaliuretic effect was relatively mild with ∼1.5 to 2‐fold increase, and the plasma K + level was unchanged . In addition, MK‐7145 enhanced the antihypertensive effect of thiazide and candesartan.…”

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

“…In particular, it would be important to compare the efficacy of MK-7145 and loop diuretics for diuretic resistance, and in patients with kidney failure. The search for Kir1.1 inhibitors has identified a limited number of compounds with appropriate potency, selectivity, and physical-chemical and pharmacokinetic properties to be used in proof of concept studies (Lewis et al, 2009;Bhave et al, 2010;Tang et al, 2012Tang et al, , 2013Tang et al, , 2016Garcia and Kaczorowski, 2014;Walsh et al, 2015Walsh et al, , 2016. MK-7145 represents the most potent and selective Kir1.1 inhibitor disclosed to date.…”

Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

“…Based on the structures of piperazine carboxamide and piperazine diamine compounds obtained from earlier screens of the Kir1.1 channel, Tang and coworkers at Merck developed MK-7145. 67 This compound displayed good Kir1.1 selectivity over other Kir channel subfamilies and selectivity over cardiac ion channels, including the ether-a-go-gorelated gene (hERG) channel. In addition, MK-7145 displayed oral bioavailability and lowered the systolic blood pressure in spontaneously hypertensive rats.…”