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Title: JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effects while maintaining bone mineral density in mice
Authors: Kurimoto, Takafumi
Tamai, Isao
Nakagawa, Takashi
Miyai, Atsuko
Yamamoto, Yasuo
Kosugi, Yoshinori
Deai, Katsuya
Hata, Takahiro
Ohta, Takeshi
Matsushita, Mutsuyoshi
Yamada, Takahisa
Author's alias: 太田, 毅
Keywords: Selective glucocorticoid receptor modulator
Collagen-induced arthritis model
Glucocorticoid-induced osteoporosis
Issue Date: 15-Mar-2021
Publisher: Elsevier BV
Journal title: European Journal of Pharmacology
Volume: 895
Thesis number: 173880
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.
Rights: © 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
The full-text file will be made open to the public on 15 March 2022 in accordance with publisher's 'Terms and Conditions for Self-Archiving'.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1016/j.ejphar.2021.173880
PubMed ID: 33476654
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