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Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators.
Vaz, Roy J; Li, Yi; Chellaraj, Vinolia; Reiling, Stephan; Kuntzweiler, Theresa; Yang, Donglai; Shen, Hong; Batchelor, Joseph D; Zhang, Ying; Chen, Xin; McLean, Larry R; Kosley, Raymond.
Afiliación
  • Vaz RJ; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA. Electronic address: roy.vaz@sanofi.com.
  • Li Y; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Chellaraj V; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Reiling S; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Kuntzweiler T; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Yang D; Pre-Development Sciences, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Shen H; Pre-Development Sciences, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Batchelor JD; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Zhang Y; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Chen X; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • McLean LR; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
  • Kosley R; Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
Bioorg Med Chem Lett ; 28(19): 3194-3196, 2018 10 15.
Article en En | MEDLINE | ID: mdl-30146095
This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5) induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric mechanism. The compounds were initially shown to induce CYP3A4/5 via the gold-standard induction assay measured in primary human hepatocytes. This was followed up by testing the compounds in a PXR assay which correlated well with the assay in primary cells. Further, one of the compounds was crystallized with PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with previously published PXR co-crystal structures, lead to modification ideas. The compounds synthesized based on these ideas were shown not to be CYP3A4/5 inducers. The mGluR2 activity of the resulting compounds was maintained.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Glutamato Metabotrópico / Citocromo P-450 CYP3A / Receptor X de Pregnano Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2018 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: Receptores de Glutamato Metabotrópico / Citocromo P-450 CYP3A / Receptor X de Pregnano Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido