The Renal Outer Medullary Potassium channel (ROMK, Kir1.1, encoded by <i>KCNJ1</i>) is a member of the inward rectifier family of potassium channels expressed in two regions of the kidney: thick ascending loop of Henle (TALH) and cortical collecting duct (CCD). Human and rodent genetic data suggest that selective inhibition of ROMK will lead to natriuresis and diuresis, representing a new class of diuretics with a novel mechanism of action and the potential for improved efficacy and tolerability. MK-7145 is the first clinical compound targeting this novel diuretic/natriuretic mechanism, where robust diuretic effects have been demonstrated in normotensive subjects in phase I studies at clinical exposures that are otherwise generally safe and well-tolerated. <br/>The ROMK backup program targets hypertension and heart failure indications, which calls for feasibility for CR and IV formulation. This requires development of basic amine containing ROMK inhibitors with excellent permeability, which will in turn contribute to increased ROMK efficacy. Generally, the major challenge of this program involves how to maintain hERG selectivity while improving permeability and PK profile. This presentation will detail SAR evolution based on spirocyclic cores and pharmacophores, which led to discovery of backup clinical candidates MK-8153 and beyond. These ROMK inhibitors have structural diversity to mitigate risk of any potential structure-based issues, and improved permeability and half-life to potentially provide a flatter, more tolerable diuresis profile, an advantage over MK-7145 and SOC loop diuretics. Novel chemistries to synthesize and utilize various spirocyclic cores will be featured in this presentation.<br/>

Discovery of MK-8153: ROMK inhibitor as new mechanism diuretic for hypertension and heart failure

2019 Fall National Meeting

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