title: The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.
abstract: The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Caryn
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey xiaoyan_zhou@merck.com mlgarciagarcia@optonline.net.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Brande
authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Martin
authors.initials: M
authors.lastname: Kohler
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Aaron
authors.initials: A
authors.lastname: Corona
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Olga
authors.initials: O
authors.lastname: Price
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Rasa
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Vince
authors.initials: V
authors.lastname: Tong
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: James
authors.initials: J
authors.lastname: Ormes
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sullivan
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.affiliation: Departments of Hypertension (C.H., X.Z., L.-Y.P., J.X., A.C., O.P., C.G., K.S., C.R., S.R., K.A.S., J.M.M., M.A.-G.), Ion Channels (B.T.P., J.P.F., B.T.-F., J.L., M.K., G.J.K., M.L.G.), Drug Metabolism (V.T., K.O., J.O.), and Medicinal Chemistry (H.T., A.P.), Merck Research Laboratories, Kenilworth, New Jersey xiaoyan_zhou@merck.com mlgarciagarcia@optonline.net.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001477:Bartter Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D001562:Benzimidazoles / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology; D008297:Male; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001572:Benzofurans; D001713:Biphenyl Compounds; C086989:KCNJ1 protein, human; C000619418:MK-7145; D010879:Piperazines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D013777:Tetrazoles; D006852:Hydrochlorothiazide; C081643:candesartan