title: Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.
abstract: Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: shawn_walsh@merck.com.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Reynalda K
authors.initials: RK
authors.lastname: de Jesus
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Nardos
authors.initials: N
authors.lastname: Teumelsan
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frie
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brochu
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Bailey
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Brande
authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Caryn
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.affiliation: Department of Safety Assessment and Lab Animal Research, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Juliann
authors.initials: J
authors.lastname: Ehrhart
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
mesh_terms: D000072237:ERG1 Potassium Channel / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D006571:Heterocyclic Compounds; C000606913:KCNH2 protein, human; D010879:Piperazines
keywords: Diuresis; Heart failure; Hypertension; Natriuresis; ROMK; hERG