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Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
Hoyt, Scott B; Park, Min K; London, Clare; Xiong, Yusheng; Tata, Jim; Bennett, D Jonathan; Cooke, Andrew; Cai, Jiaqiang; Carswell, Emma; Robinson, John; MacLean, John; Brown, Lindsay; Belshaw, Simone; Clarkson, Thomas R; Liu, Kun; Liang, Gui-Bai; Struthers, Mary; Cully, Doris; Wisniewski, Tom; Ren, Ning; Bopp, Charlene; Sok, Andrea; Cai, Tian-Quan; Stribling, Sloan; Pai, Lee-Yuh; Ma, Xiuying; Metzger, Joe; Verras, Andreas; McMasters, Daniel; Chen, Qing; Tung, Elaine; Tang, Wei; Salituro, Gino; Buist, Nicole; Kuethe, Jeff; Rivera, Nelo; Clemas, Joe; Zhou, Gaochao; Gibson, Jack; Maxwell, Carrie Ann; Lassman, Mike; McLaughlin, Theresa; Castro-Perez, Jose; Szeto, Daphne; Forrest, Gail; Hajdu, Richard; Rosenbach, Mark; Ali, Amjad.
Afiliação
  • Hoyt SB; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Park MK; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • London C; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Xiong Y; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Tata J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Bennett DJ; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Cooke A; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Cai J; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Carswell E; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Robinson J; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • MacLean J; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Brown L; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Belshaw S; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Clarkson TR; Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
  • Liu K; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Liang GB; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Struthers M; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Cully D; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Wisniewski T; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Ren N; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Bopp C; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Sok A; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Cai TQ; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Stribling S; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Pai LY; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Ma X; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Metzger J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Verras A; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • McMasters D; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Chen Q; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Tung E; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Tang W; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Salituro G; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Buist N; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Kuethe J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Rivera N; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Clemas J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Zhou G; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Gibson J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Maxwell CA; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Lassman M; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • McLaughlin T; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Castro-Perez J; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Szeto D; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Forrest G; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Hajdu R; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Rosenbach M; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
  • Ali A; Merck Research Laboratories , Rahway, New Jersey 07065, United States.
ACS Med Chem Lett ; 6(5): 573-8, 2015 May 14.
Article em En | MEDLINE | ID: mdl-26005536
ABSTRACT
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos