Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion.
Brandon J KennedyAshley M LatoAlexander R FischSusan J BurkeJustin K KirklandCarson W PrevatteLee E DunlapRussell T SmithKonstantinos D VogiatzisJ. Jason CollierShawn R CampagnaPublished in: ACS medicinal chemistry letters (2021)
Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4-substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.
Keyphrases
- anti inflammatory
- molecular docking
- multiple sclerosis
- oxidative stress
- stem cells
- gene expression
- endothelial cells
- mass spectrometry
- young adults
- transcription factor
- photodynamic therapy
- mesenchymal stem cells
- gas chromatography
- signaling pathway
- liquid chromatography
- drug induced
- tandem mass spectrometry
- light emitting
- solar cells