title: Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.
abstract: Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: yuping_zhu@merck.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhu
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: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
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: Aurash
authors.initials: A
authors.lastname: Shahripour
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pio
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
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 & Laboratory Animal Resources, 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: Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sullivan
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: D000818:Animals; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008253:Macaca mulatta; D010078:Oxazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000071230:Transcriptional Regulator ERG / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C072312:ERG protein, human; C086989:KCNJ1 protein, human; D010078:Oxazines; D024661:Potassium Channels, Inwardly Rectifying; D000071230:Transcriptional Regulator ERG
keywords: Diuresis; Heart failure; Hypertension; Natriuresis; ROMK; hERG