Effects of RS-601, a Novel Leukotriene D₄/Thromboxane A₂ Dual Receptor Antagonist, on Asthmatic Responses in Guinea Pigs

Abstract

The effects of 4-[4-[5,5,6,6,6-pentafluoro-1-(4-fluorobenzene-sulfonamido)hexyl]phenyl]butyric acid (RS-601), a novel leukotriene D₄ (LTD₄)/thromboxane A₂ (TxA₂) dual receptor antagonist, on bronchial asthmatic responses in guinea pigs were examined. The effects were compared with those of pranlukast (LTD₄ receptor antagonist) and S-1452 (TxA₂ receptor antagonist). RS-601 inhibited the increase in airway resistance caused by LTD₄ and TxA₂ mimetic compound, U-46619, but not by histamine. RS-601 and pranlukast but not S-1452 inhibited an antigen-induced late asthmatic response. In addition, RS-601 inhibited an antigen-induced airway hyperresponsiveness (AHR), whereas pranlukast and S-1452 had no effect on the AHR. The antigen-induced increase in inflammatory cells in airway was not affected by all examined agents. Furthermore, bacterial lipopolysaccharide-induced AHR in guinea pigs was clearly suppressed by RS-601 but not by pranlukast and S-1452. The increase in airway inflammatory cells caused by lipopolysaccharide was not affected by all three drugs. These findings indicate that RS-601 has a potent antiasthmatic efficacy, especially on AHR, but does not affect accumulation of eosinophils in the airways.

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…Indeed, these have been shown to be effective when used either alone or in combination for suppressing antigen-induced bronchoconstriction in guinea pigs (Yoshimi et al, 2001). Other drugs have been developed with dual leukotriene D4 and TXA 2 receptor antagonism with efficacy in experimental models of allergic inflammation (Yamada et al, 2003;Ishimura et al, 2006). However, the efficacy of TXA 2 synthase inhibitors and receptor antagonists does not spread to all inflammatory diseases where activated platelets are a component.…”

The Effects of Inhaled KP-496, a Novel Dual Antagonist for Cysteinyl Leukotriene Receptor and Thromboxane A₂ Receptor, on Allergic Asthmatic Responses in Guinea Pigs

“…KP-496 significantly inhibited AHR in this model. Another study using the same model [22] demonstrated that pranlukast and S-1452 were ineffective against AHR and that RS-601 suppressed AHR, and this suggested that both cysLTs and TXA 2 play important roles in AHR in this model. Therefore, this result was also due to both the anti-cysLT and anti-TXA 2 effects of KP-496.…”

“…Many reports have suggested that chemical mediators derived from arachidonic acid, such as cysLTs, TXA 2 and platelet-activating factor, participate in the development of LAR [3,[28][29][30] . Another group reported that pranlukast and RS-601, another dual antagonist of cysLTs and TP, suppressed LAR but that S-1452, a TP antagonist, did not suppress LAR in this model [22] . It has also been reported that a higher dose of S-1452 suppressed LAR [25] .…”

“…Since cysLTs and TXA 2 play different roles in the development and onset of asthma, inhibition of multiple pathways may yield more potent therapeutic effects. In fact, the therapeutic benefits of cysLT receptor and TP dual antagonists have been reported in guinea pig models [21,22] . These reports focused mainly on respiratory function, but there are few reports that evaluated the therapeutic effects of these antagonists by histopathological methods.…”

A Novel Dual Antagonist of Thromboxane A2 and Leukotriene D4 Receptors: Synthesis and Structure-Activity Relationships of Chloroquinolylvinyl Derivatives

“…These results suggest that an antagonist for both TXA 2 and LTD 4 receptors would be more effective in the treatment of asthma, compared to the selective antagonists. Some TXA 2 and LTD 4 dual receptor antagonists, such as RS-601 16) and YM-158, [17][18][19][20][21][22] have been reported to have potent efficacy in various antiasthmatic models.…”