ROMK (Kir1.1) is a member of the inward rectifier family of potassium channels expressed in at least two regions of the kidney: the thick ascending loop of Henle (TALH) and the cortical collecting duct (CCD). At the TALH, ROMK participates in potassium recycling across the apical (urine-facing) membrane and is essential for function of the furosemide-sensitive Na+/K+/2Cl- (NKCC2) co-transporter, the rate-determining step for sodium reuptake in this part of the nephron. At the CCD, ROMK provides a pathway for potassium secretion that is tightly coupled to sodium uptake through the amiloride-sensitive epithelial sodium channel (ENaC).  Human and rodent genetic data suggest that selective inhibition of ROMK will lead to natriuresis, diuresis and lowered blood pressure, with reduced loss of K+ in the urine. Thus, selective inhibitors of ROMK are expected to represent a new class of diuretics predicted to act at multiple sites in the nephron with a potential for greater efficacy and reduced urinary potassium excretion compared to standard-of-care loop and thiazide diuretics used in treating heart failure and hypertension.  Unfortunately, investigation of the in vitro and in vivo pharmacology of ROMK has, to date, been hampered by the absence of potent and selective ROMK inhibitors with suitable characteristics to be used in vivo as tool compounds.   The first small molecule ROMK inhibitors were reported by Denton at Vanderbilt University.  More recently, we described the discovery of a new class of potent and selective small molecule ROMK inhibitors which, remarkably, originated from a minor impurity isolated from an otherwise inactive high throughput screening hit.   This presentation will detail the discovery of our initial lead and subsequent program progress to improve ROMK potency, selectivity against the hERG channel, and poor initial PK properties. Several potent and selective benchmark ROMK inhibitors will be described in detail.  Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic characteristics in rat and dog diuresis models, and blood pressure effects in the spontaneous hypertensive rat model.  These proof-of-biology studies establish for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors.

From screening impurity to potent and selective ROMK inhibitors - the path to new mechanism diuretics

247th National Meeting (2014)

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