Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion

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.