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Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors.
Nakajima, Katsumasa; April, Myriam; Brewer, Jason T; Daniels, Thomas; Forster, Cornelia J; Gilmore, Thomas A; Jain, Monish; Kanter, Aaron; Kwak, Youngshin; Li, Jingzhou; McQuire, Les; Serrano-Wu, Michael H; Streeper, Ryan; Szklennik, Paul; Thompson, James; Wang, Bing.
Afiliación
  • Nakajima K; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • April M; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Brewer JT; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Daniels T; Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Forster CJ; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Gilmore TA; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Jain M; Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
  • Kanter A; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Kwak Y; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Li J; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • McQuire L; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Serrano-Wu MH; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Streeper R; Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Szklennik P; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Thompson J; Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  • Wang B; Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett ; 26(4): 1245-8, 2016 Feb 15.
Article en En | MEDLINE | ID: mdl-26804232
ABSTRACT
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diamida / Inhibidores Enzimáticos / Diacilglicerol O-Acetiltransferasa Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diamida / Inhibidores Enzimáticos / Diacilglicerol O-Acetiltransferasa Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos