title: JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation.
abstract: Classic glucocorticoids that have outstanding anti-inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti-inflammatory effects while reducing the occurrence of side effects, is one of the most anticipated drugs. However, there have been no SGRMs marketed to date. The assumption is that there are two major mechanisms of action of glucocorticoids via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, the anti-inflammatory effects of glucocorticoids are mostly mediated through TR, while the side effects associated with glucocorticoids are largely caused by TA. We started to evaluate novel orally available SGRMs that maintain anti-inflammatory effects while minimizing adverse effects by favoring TR over TA. Based on this evaluation, we 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. JTP-117968 has partial TR activity, but exhibits extremely low TA activity. The maximum TR efficacy of JTP-117968 was comparable to 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 that has been developed clinically as a first-in-class orally available SGRM. Remarkably, the TA activity of JTP-117968 was much weaker than PF-802 not only in in vitro assays, but also in in vivo mice experiments. These findings indicate that JTP-117968 exhibits improved TR/TA dissociation because the compound has significantly lower TA activity compared with an already reported SGRM. Therefore, JTP-117968 is expected to be a useful compound for evaluating ideal SGRMs in the future.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Electronic address: takafumi.kurimoto@jt.com.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kurimoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tamai
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Miyai
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kosugi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Deai
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Misaki
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bessho
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Negoro
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hata
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000631:Aminopyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010616:Phenanthrenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D010618:Phenanthrolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014444:Tyrosine Transaminase / Q000235:genetics
chemical_list: D000631:Aminopyridines; C000624698:JTP-117968; D010616:Phenanthrenes; D010618:Phenanthrolines; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C031181:phenanthrene; D014444:Tyrosine Transaminase
keywords: JTP-117968; Non-steroidal; Selective glucocorticoid receptor modulator (SGRM); Transactivation; Transrepression