title: The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.
abstract: A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Chobanian
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pio
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Nardos
authors.initials: N
authors.lastname: Teumelsan
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Clements
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frie
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Ferguson
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Zach
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
authors.forename: Brande S
authors.initials: BS
authors.lastname: Thomas-Fowlkes
authors.affiliation: Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
authors.forename: Martin
authors.initials: M
authors.lastname: Kohler
authors.affiliation: Department of Ion Channels, Merck & Co. Inc., Kenilworth, NJ 07033, Unites States.
authors.forename: Birgit
authors.initials: B
authors.lastname: Priest
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Caryn
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Corona
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Tong
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Joshi
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.affiliation: Department of Process Chemistry, Rahway, NJ 07065, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Maloney
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
mesh_terms: D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D004232:Diuretics; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; C510692:Kcnj1 protein, rat; D024661:Potassium Channels, Inwardly Rectifying; D013450:Sulfones
keywords: Diuresis; Heart Failure; Heterocyclic sulfone; Hypertension; Natriuresis; ROMK