Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3354-61. doi: 10.1016/j.bmcl.2007.03.103. Epub 2007 Apr 5.

Abstract

Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Bridged Bicyclo Compounds / chemistry*
  • Cell Line, Tumor
  • Glucocorticoids / chemistry*
  • Humans
  • Ligands
  • Mice
  • Models, Chemical
  • Models, Molecular
  • Pyrazoles / chemistry*
  • Receptors, Glucocorticoid / drug effects*
  • Receptors, Glucocorticoid / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds
  • Glucocorticoids
  • Ligands
  • Pyrazoles
  • Receptors, Glucocorticoid
  • pyrazole