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Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors.
Dinges, Jurgen; Harris, Christopher M; Wallace, Grier A; Argiriadi, Maria A; Queeney, Kara L; Perron, Denise C; Dominguez, Eric; Kebede, Tegest; Desino, Kelly E; Patel, Hetal; Vasudevan, Anil.
Afiliación
  • Dinges J; AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
  • Harris CM; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Wallace GA; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA.
  • Argiriadi MA; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA.
  • Queeney KL; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Perron DC; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Dominguez E; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Kebede T; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Desino KE; AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
  • Patel H; AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
  • Vasudevan A; AbbVie Inc., 1 North Waukegan Road, IL 60064, USA.
Bioorg Med Chem Lett ; 26(9): 2297-302, 2016 May 01.
Article en En | MEDLINE | ID: mdl-27020302
Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50=1.0 µM, cell IC50=1.8 µM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50=120 nM and cell potency to IC50=230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Aldehído-Liasas / Inhibidores Enzimáticos Límite: 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: 1 Bases de datos: MEDLINE Asunto principal: Aldehído-Liasas / Inhibidores Enzimáticos Límite: 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