title: Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.
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.
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Reynalda K
authors.initials: RK
authors.lastname: de Jesus
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Nardos
authors.initials: N
authors.lastname: Teumelsan
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Owens
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Brande S
authors.initials: BS
authors.lastname: Thomas-Fowlkes
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Kohler
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Bailey
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Brochu
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
keywords: KCNJ1; Kir; Kir1.1; ROMK; diuretics; hERG; heart failure; high-throughput screening (HTS); hypertension; inward rectifier; potassium channel