Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors

A Brief History of Medicinal Chemistry Approaches to Develop Novel Diuretic Therapeutics

Christopher D. Aretz, Anish K. Vadukoot, Corey R Hopkins

Research output: Contribution to journalArticle

Abstract

The renal outer medullary potassium (ROMK) channel is a member of the inwardly rectifying family of potassium (Kir, Kir1.1) channels. It is primarily expressed in two regions of the kidney, the cortical collecting duct (CCD) and the thick ascending loop of Henle (TALH). At the CCD it tightly regulates potassium secretion while controlling potassium recycling in TALH. As loss-of-function mutations lead to salt wasting and low blood pressure, it has been surmised that inhibitors of ROMK would represent a target for new and improved diuretics for the treatment of hypertension and heart failure. In this review, we discuss and provide an overview of the medicinal chemistry approaches toward the development of small molecule ROMK inhibitors over the past decade.

Original languageEnglish (US)
Pages (from-to)8682-8694
Number of pages13
JournalJournal of Medicinal Chemistry
Volume62
Issue number19
DOIs
StatePublished - Oct 10 2019

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Loop of Henle
Pharmaceutical Chemistry
Potassium Channels
Diuretics
Potassium
Collecting Kidney Tubules
Kidney
Recycling
Treatment Failure
Hypotension
Heart Failure
Salts
Hypertension
Mutation
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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title = "Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches to Develop Novel Diuretic Therapeutics",
abstract = "The renal outer medullary potassium (ROMK) channel is a member of the inwardly rectifying family of potassium (Kir, Kir1.1) channels. It is primarily expressed in two regions of the kidney, the cortical collecting duct (CCD) and the thick ascending loop of Henle (TALH). At the CCD it tightly regulates potassium secretion while controlling potassium recycling in TALH. As loss-of-function mutations lead to salt wasting and low blood pressure, it has been surmised that inhibitors of ROMK would represent a target for new and improved diuretics for the treatment of hypertension and heart failure. In this review, we discuss and provide an overview of the medicinal chemistry approaches toward the development of small molecule ROMK inhibitors over the past decade.",
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