Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion
Document Type
Article
Publication Date
10-14-2021
Abstract
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.
Recommended Citation
Kennedy, B., Lato, A., Fisch, A., Burke, S., Kirkland, J., Prevatte, C., Dunlap, L., Smith, R., Vogiatzis, K., Collier, J., & Campagna, S. (2021). Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion. Retrieved from https://repository.lsu.edu/pbrc_basic_science_pubs/74