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Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics.
Tang, Haifeng; Walsh, Shawn P; Yan, Yan; de Jesus, Reynalda K; Shahripour, Aurash; Teumelsan, Nardos; Zhu, Yuping; Ha, Sookhee; Owens, Karen A; Thomas-Fowlkes, Brande S; Felix, John P; Liu, Jessica; Kohler, Martin; Priest, Birgit T; Bailey, Timothy; Brochu, Richard; Alonso-Galicia, Magdalena; Kaczorowski, Gregory J; Roy, Sophie; Yang, Lihu; Mills, Sander G; Garcia, Maria L; Pasternak, Alexander.
Afiliación
  • Tang H; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Walsh SP; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Yan Y; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • de Jesus RK; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Shahripour A; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Teumelsan N; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Zhu Y; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Ha S; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Owens KA; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Thomas-Fowlkes BS; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Felix JP; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Liu J; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Kohler M; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Priest BT; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Bailey T; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Brochu R; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Alonso-Galicia M; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Kaczorowski GJ; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Roy S; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Yang L; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Mills SG; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Garcia ML; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
  • Pasternak A; Departments of Medicinal Chemistry, Hypertension, Ion Channels, Preclinical DMPK, and Chemistry Modeling, Merck Research Laboratories , Rahway New Jersey 07065, United States.
ACS Med Chem Lett ; 3(5): 367-72, 2012 May 10.
Article en En | MEDLINE | ID: mdl-24900480
ABSTRACT
The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure-activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA