title: Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation.
abstract: A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Nardos
authors.initials: N
authors.lastname: Teumelsan
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frie
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Margulis
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Visconti
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Weinglass
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brochu
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Bailey
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Brande
authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Corona
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Caryn
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ross
authors.initials: R
authors.lastname: Bentley
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Forrest
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Tong
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Parmee
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Discovery Chemistry, Department of Pharmacology, Department of Cardiometabolic Diseases, Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Department of Chemistry Modeling and Informatics, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
keywords: ROMK; diuresis; heart failure; hypertension; natriuresis