Kurimoto Takafumi, Tamai Isao, Miyai Atsuko, Kosugi Yoshinori, Nakagawa Takashi, Yamamoto Yasuo, Deai Katsuya, Misaki Shohei, Bessho Yuki, Negoro Tamotsu, Yamaguchi Takayuki, Hata Takahiro, Matsushita Mutsuyoshi
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Eur J Pharmacol. 2017 May 15;803:179-186. doi: 10.1016/j.ejphar.2017.03.057. Epub 2017 Mar 31.
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.
具有出色抗炎作用的经典糖皮质激素仍被广泛用于治疗各种炎症和自身免疫性疾病。相反，糖皮质激素会引发众多不良副作用，尤其是全身给药的糖皮质激素。因此，选择性糖皮质激素受体调节剂（SGRM）在维持有益抗炎作用的同时减少副作用的发生，是最受期待的药物之一。然而，迄今为止尚无已上市的SGRM。一般认为，糖皮质激素通过糖皮质激素受体有两种主要作用机制，即反式抑制（TR）和反式激活（TA）。通常，糖皮质激素的抗炎作用主要通过TR介导，而与糖皮质激素相关的副作用很大程度上由TA引起。我们开始评估新型口服可用的SGRM，其通过优先选择TR而非TA来维持抗炎作用，同时将不良反应降至最低。基于此评估，我们发现了JTP-117968，即(4b'S,7'R,8a'S)-4b'-苄基-7'-羟基-N-(2-甲基吡啶-3-基)-7'-(三氟甲基)-4b',6',7',8',8a',10'-六氢-5'H-螺[环丙烷-1,9'-菲]-2'-甲酰胺，一种非甾体SGRM。JTP-117968具有部分TR活性，但TA活性极低。JTP-117968的最大TR效能与其结构类似物PF-802，即(4bS,7R,8aR)-4b-苄基-7-羟基-N-(2-甲基吡啶-3-基)-7-(三氟甲基)-4b,5,6,7,8,8a,9,10-八氢菲-2-甲酰胺相当，PF-802是已作为首个口服可用的SGRM在临床上开发的Fosdagrocorat的活性形式。值得注意的是，JTP-117968的TA活性不仅在体外试验中，而且在体内小鼠实验中都比PF-802弱得多。这些发现表明JTP-117968表现出改善的TR/TA解离，因为与已报道的SGRM相比，该化合物的TA活性显著更低。因此，预计JTP-117968在未来将成为评估理想SGRM的有用化合物。
