Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity

J Med Chem. 2004 May 6;47(10):2441-52. doi: 10.1021/jm030585i.

Abstract

A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Enzyme Induction
  • Female
  • Glutamate-Ammonia Ligase / biosynthesis
  • Glutamate-Ammonia Ligase / genetics
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Interleukin-6 / antagonists & inhibitors
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Molecular Conformation
  • Protein Isoforms / agonists
  • Protein Isoforms / metabolism
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Radioligand Assay
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Transcription, Genetic / drug effects
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tyrosine Transaminase / biosynthesis
  • Tyrosine Transaminase / genetics

Substances

  • 1-(3-thienyl)(1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo(f)indazol-5-yl)methanone
  • 1-(4-fluorophenyl)-1-(1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo(f)indazol-5-yl)ethanol
  • Anti-Inflammatory Agents, Non-Steroidal
  • Indazoles
  • Interleukin-6
  • Ligands
  • Protein Isoforms
  • Pyrazoles
  • Receptors, Glucocorticoid
  • Thiophenes
  • Tumor Necrosis Factor-alpha
  • Tyrosine Transaminase
  • Glutamate-Ammonia Ligase