{"created":"2022-07-15T00:45:55.976136+00:00","id":2000621,"links":{},"metadata":{"_buckets":{"deposit":"01443700-a580-4850-b8d1-5bbcd791dbdf"},"_deposit":{"id":"2000621","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"2000621"},"status":"published"},"_oai":{"id":"oai:niigata-u.repo.nii.ac.jp:02000621","sets":["453:455","468:563:564"]},"author_link":[],"item_6_date_granted_51":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2022-03-23"}]},"item_6_degree_grantor_49":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_language":"ja","subitem_degreegrantor_name":"新潟大学"},{"subitem_degreegrantor_language":"en","subitem_degreegrantor_name":"Niigata University"}],"subitem_degreegrantor_identifier":[{"subitem_degreegrantor_identifier_name":"13101","subitem_degreegrantor_identifier_scheme":"kakenhi"}]}]},"item_6_degree_name_48":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士（農学）","subitem_degreename_language":"ja"}]},"item_6_description_4":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Classic glucocorticoids, such as prednisolone and dexamethasone, are widely prescribed to treat diverse autoimmune and inflammatory diseases, including rheumatic arthritis and systemic lupus erythematosus. Conversely, classic glucocorticoids cause harmful side effects such as osteoporosis, diabetes, central obesity, hypertension and many others, particularly during systemic administration. The side effects mentioned above limit the dose and duration of treatment with classic glucocorticoids. Therefore, selective glucocorticoid receptor modulators (SGRMs), which retain beneficial anti-inflammatory effects but reduce the occurrence of side effects, are among the most anticipated drugs in the clinical field. Glucocorticoids regulate a wide variety of gene expressions through glucocorticoid receptor (GR) which controls gene transcriptions via multiple and complex mechanisms. The assumption is that there are two major mechanisms of action of GR: one being via transactivation (TA), through activation of mRNA expression of various molecules such as tyrosine aminotransferase via glucocorticoid response elements (GRE), and the other via transrepression (TR), through interference in the binding of transcription factors, such as Nuclear Factor kappa B, to a transcription site of mRNA that is independent of GRE. Although several reports suggest that some anti-inflammatory proteins are induced by TA activity, it is generally believed that anti-inflammatory effects of classic glucocorticoids are largely due to TR, while the problematic side effects associated with classic glucocorticoids are mediated through TA. Over the past few decades, numerous efforts have been made in the development of SGRMs that retain anti-inflammatory effects while minimizing side effects by favoring TR over TA activity via GR. One of the drug candidates, fosdagrocorat, has been developed clinically as an orally available SGRM that was reported to show efficacy in patients with moderate to severe rheumatoid arthritis comparable to prednisone. However, none of these SGRMs have been approved and marketed to date. Recently, Central Pharmaceutical Research Institute within Japan Tobacco Inc. discovered JTP-117968, (4b'S,7'R,8a'S)-4b'-benzyl-7'-hydroxy-N-(2-methylpyridin-3-yl)-7'-(trifluoromethyl)-4b',6',7',8',8a',10'-hexahydro-5'H-spiro[cyclopropane-1,9'-phenanthrene]-2'-carboxamide, a non-steroidal SGRM. In the present study, we first confirmed that JTP-117968 showed highly selective and potent GR binding affinity. Unlike classic glucocorticoids, JTP-117968 had neither agonist nor antagonist activity against mineralocorticoid receptor. We also confirmed that JTP-117968 maintained partial TR activity while remarkably reducing the TA activity. The maximum TR efficacy of JTP-117968 was slightly lower than its structural analogue, PF-802, (4bS,7R,8aR)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide, which is the active form of fosdagrocorat. Notably, the TA activity of JTP-117968 was much weaker than those of prednisolone and PF-802. Next, we evaluated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model in mice. We confirmed that JTP-117968 showed the significant inhibitory effect on tumor necrosis factor α release elicited in LPS-injected mice and exhibited partial TR activity in in vivo experiments in line with the result from in vitro assay. Then, we also evaluated the effect of JTP-117968 on the mouse collagen-induced arthritis (CIA) model. Remarkably, JTP-117968 showed an almost completely suppressive effect against the development of arthritis. In addition to the arthritis score, JTP-117968 inhibited the increase in the relative spleen weight in mouse CIA model completely. We also found that PF-802 showed the inhibitory effect on the development of arthritis and the increase in the relative spleen weight in the mouse CIA model comparably with prednisolone. In the clinical trials, fosdagrocorat was demonstrated as showing efficacy in rheumatoid arthritis patients comparable to that of prednisolone. Hence, JTP-117968, which has partial TR activity, is expected to exhibit anti-inflammatory effect against rheumatoid arthritis comparable to that of classic glucocorticoids. Finally, we examined the effect of JTP-117968, which has exceedingly low TA activity, on the mouse bone metabolism to evaluate the side effect. It is reported that daily oral glucocorticoids treatment leads to a reduction in bone mineral density (BMD) and a rapid increase in the risk of fracture during the treatment period. Therefore, we evaluated the effect of JTP-117968 on the BMD in normal mouse femur. In our experiment, we confirmed that prednisolone reduced the BMD in mouse femur after 28 days of repeated oral administration as reported previously. Strikingly, JTP-117968 hardly altered the BMD in mouse femur after 28 days of repeated dosing. Meanwhile, PF-802 showed the tendency to reduce the BMD in mice. It is assumed that glucocorticoid-induced osteoporosis is mainly caused by reduction of osteoblastic bone formation. In human osteoblasts, classic glucocorticoids increase the expression of Dickkopf-1 (Dkk-1), which negatively regulates bone formation via a TA mechanism. As JTP-117968 hardly reduced the BMD in mouse femur, we examined the Dkk-1 induction activity of JTP-117968 in human primary osteoblasts. Based on the evaluation, JTP-117968 barely induced Dkk-1 mRNA expression in comparison with prednisolone. Remarkably, the Dkk-1 induction activity of JTP-117968 was even lower than that of PF-802. Therefore, JTP-117968, with minimized TA activity, is expected to have less side effects on bone formation in humans compared with classic glucocorticoids and already reported SGRMs. In summary, our data demonstrated that JTP-117968, a novel SGRM that maintained the partial TR activity while remarkably reducing the TA activity, has attractive potential as a new therapeutic option against inflammatory and autoimmune diseases, such as rheumatoid arthritis, with minimized side effects compared to classic glucocorticoids.","subitem_description_language":"en","subitem_description_type":"Abstract"}]},"item_6_description_53":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"新大院博(農)第220号","subitem_description_language":"ja","subitem_description_type":"Other"}]},"item_6_dissertation_number_52":{"attribute_name":"学位授与番号","attribute_value_mlt":[{"subitem_dissertationnumber":"甲第5060号"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_abf2"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"栗本, 貴史","creatorNameLang":"ja"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"date":[{"dateType":"Available","dateValue":"2022-07-15"}],"displaytype":"detail","filename":"r3fak220.pdf","filesize":[{"value":"1.98MB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"本文","objectType":"fulltext","url":"https://niigata-u.repo.nii.ac.jp/record/2000621/files/r3fak220.pdf"},"version_id":"d8c57a5c-3464-46d0-a2fb-912a3a975983"},{"date":[{"dateType":"Available","dateValue":"2022-07-15"}],"displaytype":"detail","filename":"r3fak220_a.pdf","filesize":[{"value":"118KB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"要旨","objectType":"abstract","url":"https://niigata-u.repo.nii.ac.jp/record/2000621/files/r3fak220_a.pdf"},"version_id":"ee39710c-00f7-46fc-8aa0-8ff5097582b7"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"doctoral thesis","resourceuri":"http://purl.org/coar/resource_type/c_db06"}]},"item_title":"生体における新規Selective Glucocorticoid Receptor Modulator(JTP-117968)の抗炎症作用および副作用の評価に関する研究","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"生体における新規Selective Glucocorticoid Receptor Modulator(JTP-117968)の抗炎症作用および副作用の評価に関する研究","subitem_title_language":"ja"}]},"item_type_id":"6","owner":"1","path":["455","564"],"pubdate":{"attribute_name":"PubDate","attribute_value":"2022-07-15"},"publish_date":"2022-07-15","publish_status":"0","recid":"2000621","relation_version_is_last":true,"title":["生体における新規Selective Glucocorticoid Receptor Modulator(JTP-117968)の抗炎症作用および副作用の評価に関する研究"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2022-12-15T04:17:52.889118+00:00"}