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Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors.
Barnes-Seeman, David; Boiselle, Carri; Capacci-Daniel, Christina; Chopra, Rajiv; Hoffmaster, Keith; Jones, Christopher T; Kato, Mitsunori; Lin, Kai; Ma, Sue; Pan, Guoyu; Shu, Lei; Wang, Jianling; Whiteman, Leah; Xu, Mei; Zheng, Rui; Fu, Jiping.
Afiliación
  • Barnes-Seeman D; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Boiselle C; Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Capacci-Daniel C; Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Chopra R; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Hoffmaster K; Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Jones CT; Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
  • Kato M; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Lin K; Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
  • Ma S; Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
  • Pan G; Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Shu L; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Wang J; Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Whiteman L; Department of Infectious Diseases, Novartis Institutes for BioMedical Research, 500 Technology Square, Cambridge, MA 02139, United States.
  • Xu M; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Zheng R; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.
  • Fu J; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States. Electronic address: jiping.fu@novartis.com.
Bioorg Med Chem Lett ; 24(16): 3979-85, 2014 Aug 15.
Article en En | MEDLINE | ID: mdl-24986660
Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / ARN Polimerasa Dependiente del ARN / Ácidos Carboxílicos / Diseño de Fármacos / Proteínas no Estructurales Virales / Inhibidores Enzimáticos Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / ARN Polimerasa Dependiente del ARN / Ácidos Carboxílicos / Diseño de Fármacos / Proteínas no Estructurales Virales / Inhibidores Enzimáticos Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido