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Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2004 May 06; Vol. 47 (10), pp. 2441-52. - Publication Year :
- 2004
-
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.
- Subjects :
- Animals
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 chemistry
Indazoles pharmacology
Interleukin-6 antagonists & inhibitors
Ligands
Mice
Mice, Inbred BALB C
Molecular Conformation
Protein Isoforms agonists
Protein Isoforms metabolism
Pyrazoles chemistry
Pyrazoles pharmacology
Radioligand Assay
Receptors, Glucocorticoid agonists
Stereoisomerism
Structure-Activity Relationship
Thiophenes chemistry
Thiophenes pharmacology
Transcription, Genetic drug effects
Transcriptional Activation drug effects
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tyrosine Transaminase biosynthesis
Tyrosine Transaminase genetics
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
Indazoles chemical synthesis
Pyrazoles chemical synthesis
Receptors, Glucocorticoid metabolism
Thiophenes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 47
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15115388
- Full Text :
- https://doi.org/10.1021/jm030585i