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Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety.
He, Shuwen; Lai, Zhong; Hong, Qingmei; Shang, Jackie; Reibarkh, Mikhail; Kuethe, Jeffrey T; Liu, Jian; Guiadeen, Deodial; Krikorian, Arto D; Cernak, Timothy A; Dykstra, Kevin D; Sperbeck, Donald M; Wu, Zhicai; Yu, Yang; Yang, Ginger X; Jian, Tianying; Verras, Andreas; Sonatore, Lisa M; Wiltsie, Judyann; Chung, Christine C; Murphy, Beth A; Gorski, Judith N; Liu, Jinqi; Xiao, Jianying; Wolff, Michael; Tong, Sharon X; Madeira, Maria; Karanam, Bindhu V; Shen, Dong-Ming; Balkovec, James M; Pinto, Shirly; Nargund, Ravi P; DeVita, Robert J.
Afiliación
  • He S; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: shuwen@kallyope.com.
  • Lai Z; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Hong Q; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Shang J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Reibarkh M; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Kuethe JT; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Liu J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Guiadeen D; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Krikorian AD; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Cernak TA; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Dykstra KD; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Sperbeck DM; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Wu Z; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Yu Y; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Yang GX; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Jian T; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Verras A; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Sonatore LM; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Wiltsie J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Chung CC; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Murphy BA; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Gorski JN; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Liu J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Xiao J; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Wolff M; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Tong SX; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Madeira M; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Karanam BV; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Shen DM; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Balkovec JM; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Pinto S; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • Nargund RP; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
  • DeVita RJ; Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Bioorg Med Chem Lett ; 29(10): 1182-1186, 2019 05 15.
Article en En | MEDLINE | ID: mdl-30926247
Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bencimidazoles / Ácidos Carboxílicos / Inhibidores Enzimáticos / Diacilglicerol O-Acetiltransferasa Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bencimidazoles / Ácidos Carboxílicos / Inhibidores Enzimáticos / Diacilglicerol O-Acetiltransferasa Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido