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Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides.
Serrano-Wu, Michael H; Coppola, Gary M; Gong, Yongjin; Neubert, Alan D; Chatelain, Ricardo; Clairmont, Kevin B; Commerford, Renee; Cosker, Theresa; Daniels, Thomas; Hou, Ying; Jain, Monish; Juedes, Marlene; Li, Lisha; Mullarkey, Tara; Rocheford, Erik; Sung, Moo Je; Tyler, Andrew; Yang, Qing; Yoon, Taeyoung; Hubbard, Brian K.
Afiliação
  • Serrano-Wu MH; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Coppola GM; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Gong Y; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Neubert AD; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Chatelain R; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Clairmont KB; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Commerford R; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Cosker T; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Daniels T; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Hou Y; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Jain M; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Juedes M; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Li L; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Mullarkey T; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Rocheford E; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Sung MJ; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Tyler A; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Yang Q; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Yoon T; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
  • Hubbard BK; Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
ACS Med Chem Lett ; 3(5): 411-5, 2012 May 10.
Article em En | MEDLINE | ID: mdl-24900485
ABSTRACT
High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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: 2012 Tipo de documento: Article País de afiliação: Estados Unidos