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

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.

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation.

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.

Orally administered selective TRPV1 antagonist, JTS-653, attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain.

Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1-inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain.

Role of histamine H3 receptors during ischemia/reperfusion in isolated rat hearts.

Histamine H3 receptors are involved in regulating the release of norepinephrine (NE), in both central and peripheral nervous systems. We investigated the effect of R-alpha-methylhistamine (R-HA), a selective H3 receptor agonist, and thioperamide (Thiop), a selective H3 receptor antagonist, on ischemia/reperfusion-induced changes in carrier-mediated NE release and cardiac function in isolated rat heart. Hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Ischemia/reperfusion evoked massive NE release, which was markedly suppressed by the treatment with desipramine (DMI), a neuronal NE transporter blocker. Ischemia/reperfusion-induced cardiac dysfunction (decreases in left ventricular developed pressure, LVDP, and the first derivative of left ventricular pressure, dP/dt, and a rise in left ventricular end diastolic pressure, LVEDP) was also improved by the DMI treatment. The treatment with R-HA also significantly decreased the excessive NE release induced by the ischemia/reperfusion, improved the recovery of LVDP and dP/dt, and suppressed the rise in LVEDP. Thiop did not affect NE release and cardiac function after the reperfusion. When R-HA was administered concomitantly with Thiop, R-HA failed to attenuate ischemia/reperfusion-induced NE release and cardiac dysfunction. Thus, it seems likely that the ischemia/reperfusion-induced carrier-mediated NE release in rat hearts is negatively regulated by the activation of H3 receptors, probably located on cardiac noradrenergic nerve endings.