Classic
glucocorticoids have been prescribed for various inflammatory diseases, such as
rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However,
glucocorticoids cause numerous unwanted side effects, including
osteoporosis and diabetes. Hence, selective
glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via
glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of
glucocorticoids are largely due to TR, while the side effects associated with
glucocorticoids are mostly mediated through TA. We previously reported that
JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of
JTP-117968 on a
lipopolysaccharide (LPS) challenge model and
collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of
JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation,
JTP-117968 reduced the plasma levels of
tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by
JTP-117968 comparably with
prednisolone and
PF-802, an active form of
fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of
JTP-117968 on mouse femoral BMD was much lower than those of
PF-802 and
prednisolone. Therefore,
JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic
glucocorticoids.