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  • Recent pharmaceutical research in the field of respiratory d

    2020-03-25

    Recent pharmaceutical research in the field of respiratory diseases has sought to make available new agents that specifically and selectively antagonize the actions of cysteinyl–leukotrienes. Such an effort has resulted in the development of two classes of drugs, effective in counteracting Cys-LTs pathway, that are now offered for the treatment of asthma: LTD4 receptor antagonists (montelukast, pranlukast, and zafirlukast) and leukotriene synthesis inhibitors (zileuton; Brooks and Summers, 1996). Cysteinyl–leukotrienes act via two different G-protein-coupled receptors, leukotrienes CysLT1 and leukotriene CysLT2 (Gorenne et al., 1996, Heise et al., 2000). The former appears to be the primary regulator of the deleterious effects that cysteinyl–leukotrienes exert on human airways because selective antagonism of leukotriene CysLT1 receptor, by means of the previously cited compounds, has been shown to improve both 490 symptoms (Suissa et al., 1997) and the underlying inflammatory response (Nakamura et al., 1998). In the clinical setting, leukotriene CysLT1 receptor antagonists were demonstrated to be effective for the treatment of mild to moderate asthma, particularly that associated with inhaled steroid and β-adrenergic agonist therapies (Liu et 490 al., 1996). Moreover, they are highly efficacious in the prevention of exercise-induced bronchoconstriction, and can be used in aspirin-intolerant asthmatic subjects (Manning et al., 1990, Dahlen et al., 1993). This manuscript illustrates the preclinical pharmacological profile of CR3465 (l-Tyrosine, N-[(2-quinolinyl)carbonyl]-O-(7-fluoro-2-quinolinylmethyl) sodium salt), a new potent and selective leukotriene Cys-LT1 receptor antagonist synthesized by Makovec et al. (2001). CR3465 also has additional antiinflammatory activities; altogether, these characteristics are suggestive of a potential use for CR3465 in the treatment of pathologies affecting the respiratory system.
    Methods
    Results
    Discussion CR3465 is a potent and selective compound designed to specifically antagonize leukotriene CysLT1 receptor. When comparing our results with those reported in previous publications (Krell et al., 1990, Francis et al., 1998), its core pharmacological profile appears to be similar, or even improved, with respect to other chemical entities belonging to the same class. In guinea pig lung parenchymal membranes, CR3465 antagonized [3H]LTD4 binding with a Ki of 4.7 nM (montelukast, Ki=5.6 nM). The higher montelukast Ki value, as compared with that reported by others (Jones et al., 1994, Cabré et al., 2002), can most likely be ascribed to diverse experimental conditions, as also confirmed by similarly observed differences in terms of [3H]LTD4Kd. Nonetheless, because montelukast and CR3465 were evaluated within the same set of experiments, we believe that a direct comparison between the binding affinities of the two compounds is valid and reliable. In isolated guinea pig trachea, CR3465 behaved as an entirely competitive antagonist, causing parallel rightward shifts in the concentration–response curve observed in the presence of LTD4, and without altering maximal contractile response to the agonist. Conversely montelukast, at the higher concentrations tested (100–1000 nM), significantly lowered the upper plateau of the curve, although this phenomenon was not previously observed by other investigators (Jones et al., 1994). Next, a series of studies in anesthetized guinea pig demonstrated that intravenous administration of CR3465 effectively antagonized/reverted the in vivo LTD4-induced bronchoconstriction. These findings in guinea pig airways clearly indicate that CR3465 exhibits a leukotriene CysLT1 receptor antagonist activity similar or even greater than that of the reference compound montelukast, both in terms of potency and efficacy. Because potential species-related differences in affinity were reported in binding studies (Aharony, 1998), we understand that these data need to be further confirmed in human tissues.