title: Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.
abstract: ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Nardos
authors.initials: N
authors.lastname: Teumelsan
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brochu
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Bailey
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Brande
authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Caryn
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Corona
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Forrest
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Tong
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Parmee
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Departments of Discovery Chemistry, Ion Channels, In Vivo Pharmacology, Cardiorenal, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
keywords: MK-7145; ROMK; diuretics; heart failure; hypertension; natriuresis