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The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.
Hampton, Caryn; Zhou, Xiaoyan; Priest, Birgit T; Pai, Lee-Yuh; Felix, John P; Thomas-Fowlkes, Brande; Liu, Jessica; Kohler, Martin; Xiao, Jianying; Corona, Aaron; Price, Olga; Gill, Charles; Shah, Kashmira; Rasa, Cordelia; Tong, Vince; Owens, Karen; Ormes, James; Tang, Haifeng; Roy, Sophie; Sullivan, Kathleen A; Metzger, Joseph M; Alonso-Galicia, Magdalena; Kaczorowski, Gregory J; Pasternak, Alexander; Garcia, Maria L.
Afiliação
  • Hampton C; 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,
  • Zhou X; 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,
  • Priest BT; 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,
  • Pai LY; 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,
  • Felix JP; 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,
  • Thomas-Fowlkes B; 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,
  • Liu J; 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,
  • Kohler M; 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,
  • Xiao J; 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,
  • Corona A; 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,
  • Price O; 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,
  • Gill C; 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,
  • Shah K; 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,
  • Rasa C; 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,
  • Tong V; 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,
  • Owens K; 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,
  • Ormes J; 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,
  • Tang H; 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,
  • Roy S; 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,
  • Sullivan KA; 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,
  • Metzger JM; 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,
  • Alonso-Galicia M; 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,
  • Kaczorowski GJ; 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,
  • Pasternak A; 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,
  • Garcia ML; 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,
J Pharmacol Exp Ther ; 359(1): 194-206, 2016 10.
Article em En | MEDLINE | ID: mdl-27432892
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fenótipo / Piperazinas / Síndrome de Bartter / Benzofuranos / Pressão Sanguínea / Canais de Potássio Corretores do Fluxo de Internalização / Bloqueadores dos Canais de Potássio Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fenótipo / Piperazinas / Síndrome de Bartter / Benzofuranos / Pressão Sanguínea / Canais de Potássio Corretores do Fluxo de Internalização / Bloqueadores dos Canais de Potássio Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article