1. JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effects while maintaining bone mineral density in mice
- Author
-
Mutsuyoshi Matsushita, Takahisa Yamada, Yoshinori Kosugi, Takeshi Ohta, Takashi Nakagawa, Takahiro Hata, Takafumi Kurimoto, Katsuya Deai, Atsuko Miyai, Yasuo Yamamoto, and Isao Tamai
- Subjects
0301 basic medicine ,Male ,Side effect ,Lipopolysaccharide ,Prednisolone ,Anti-Inflammatory Agents ,Arthritis ,Aminopyridines ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Glucocorticoid receptor ,Receptors, Glucocorticoid ,Bone Density ,medicine ,Fosdagrocorat ,Animals ,Humans ,Glucocorticoids ,JTP-117968 ,Transrepression ,Mice, Inbred BALB C ,Osteoblasts ,Glucocorticoid-induced osteoporosis ,business.industry ,Tumor Necrosis Factor-alpha ,PF-802 ,medicine.disease ,Arthritis, Experimental ,030104 developmental biology ,chemistry ,Collagen-induced arthritis model ,Mice, Inbred DBA ,Rheumatoid arthritis ,Intercellular Signaling Peptides and Proteins ,Selective glucocorticoid receptor modulator ,Female ,Joints ,Inflammation Mediators ,business ,030217 neurology & neurosurgery ,medicine.drug ,Phenanthrolines - Abstract
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.
- Published
- 2021