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JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits significant anti-inflammatory effect while maintaining bone mineral density in mice.

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.
AuthorsTakafumi Kurimoto, Isao Tamai, Takashi Nakagawa, Atsuko Miyai, Yasuo Yamamoto, Yoshinori Kosugi, Katsuya Deai, Takahiro Hata, Takeshi Ohta, Mutsuyoshi Matsushita, Takahisa Yamada
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 895 Pg. 173880 (Mar 15 2021) ISSN: 1879-0712 [Electronic] Netherlands
PMID33476654 (Publication Type: Comparative Study, Journal Article)
CopyrightCopyright © 2021 Elsevier B.V. All rights reserved.
Chemical References
  • Aminopyridines
  • Anti-Inflammatory Agents
  • DKK1 protein, human
  • Glucocorticoids
  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • JTP-117968
  • Phenanthrolines
  • Receptors, Glucocorticoid
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha
Topics
  • Aminopyridines (pharmacology, toxicity)
  • Animals
  • Anti-Inflammatory Agents (pharmacology, toxicity)
  • Arthritis, Experimental (metabolism, pathology, prevention & control)
  • Bone Density (drug effects)
  • Female
  • Glucocorticoids (pharmacology, toxicity)
  • Humans
  • Inflammation Mediators (blood)
  • Intercellular Signaling Peptides and Proteins (genetics, metabolism)
  • Joints (drug effects, metabolism, pathology)
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Osteoblasts (drug effects, metabolism)
  • Phenanthrolines (pharmacology, toxicity)
  • Receptors, Glucocorticoid (agonists, metabolism)
  • Tumor Necrosis Factor-alpha (blood)

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