Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

ACS Med Chem Lett. 2012 Mar 28;3(5):367-72. doi: 10.1021/ml3000066.

Haifeng Tang ¹, Shawn P Walsh ¹, Yan Yan ¹, Reynalda K de Jesus ¹, Aurash Shahripour ¹, Nardos Teumelsan ¹, Yuping Zhu ¹, Sookhee Ha ¹, Karen A Owens ¹, Brande S Thomas-Fowlkes ¹, John P Felix ¹, Jessica Liu ¹, Martin Kohler ¹, Birgit T Priest ¹, Timothy Bailey ¹, Richard Brochu ¹, Magdalena Alonso-Galicia ¹, Gregory J Kaczorowski ¹, Sophie Roy ¹, Lihu Yang ¹, Sander G Mills ¹, Maria L Garcia ¹, Alexander Pasternak ¹

Affiliations

Affiliation

1 Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.

PMID: 24900480 DOI: 10.1021/ml3000066

Abstract

The renal outer medullary Potassium Channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure-activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against Other members of the inward rectifier family of potassium channels.

Keywords

KCNJ1; Kir; Kir1.1; ROMK; diuretics; hERG; heart failure; high-throughput screening (HTS); hypertension; inward rectifier; potassium channel.

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