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Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.
Zhu, Yuping; de Jesus, Reynalda K; Tang, Haifeng; Walsh, Shawn P; Jiang, Jinlong; Gu, Xin; Teumelsan, Nardos; Shahripour, Aurash; Pio, Barbara; Ding, Fa-Xiang; Ha, Sookhee; Priest, Birgit T; Swensen, Andrew M; Alonso-Galicia, Magdalena; Felix, John P; Brochu, Richard M; Bailey, Timothy; Thomas-Fowlkes, Brande; Zhou, Xiaoyan; Pai, Lee-Yuh; Hampton, Caryn; Hernandez, Melba; Owens, Karen; Ehrhart, Juliann; Roy, Sophie; Kaczorowski, Gregory J; Yang, Lihu; Parmee, Emma R; Sullivan, Kathleen; Garcia, Maria L; Pasternak, Alexander.
Afiliación
  • Zhu Y; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: yuping_zhu@merck.com.
  • de Jesus RK; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Tang H; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Walsh SP; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Jiang J; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Gu X; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Teumelsan N; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Shahripour A; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Pio B; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Ding FX; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Ha S; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Priest BT; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Swensen AM; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Alonso-Galicia M; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Felix JP; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Brochu RM; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Bailey T; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Thomas-Fowlkes B; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Zhou X; Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Pai LY; Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Hampton C; Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Hernandez M; Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Owens K; Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Ehrhart J; Department of Safety Assessment & Laboratory Animal Resources, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Roy S; Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Kaczorowski GJ; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Yang L; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Parmee ER; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Sullivan K; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Garcia ML; Department of Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
  • Pasternak A; Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
Bioorg Med Chem Lett ; 26(23): 5695-5702, 2016 12 01.
Article en En | MEDLINE | ID: mdl-27839686
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazinas / Canales de Potasio de Rectificación Interna Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazinas / Canales de Potasio de Rectificación Interna Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article