Targeting the inward-rectifier potassium channel ROMK in cardiovascular disease

• Rodent and human genetics support ROMK as a novel diuretic target.
• High throughput screens have discovered novel small molecule inhibitor leads.
• Two inhibitors with some structural similarity have been independently identified.
• Medicinal chemistry has demonstrated tractability of one lead for drug development.
• Proof of concept for ROMK as a drug target has been demonstrated with these agents.

The kidney plays a critical role in blood pressure homeostasis as a result of the integrated activity of different mechanisms that ensure proper salt and water reabsorption. Diuretics, developed more than four decades ago, are used to treat hypertension and/or congestive heart failure, although there are therapeutic issues that limit their use. Human and rodent genetic studies provide a large body of evidence which suggests that inhibitors of the kidney potassium channel, ROMK, will represent novel diuretics for the treatment of hypertension. The search for potent and selective ROMK inhibitors has recently yielded compounds that display efficacy in animal models, providing the first pharmacological validation of ROMK as a novel diuretic target.