This manuscript illustrates the preclinical pharmacological

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 nelfinavir 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. Such concerns do not apply to the anti-inflammatory actions shown by the agent, given that CR3465 proved effective in various models of inflammation including guinea pig, rat, and human. Airway inflammation, involving a complex network of local mediators, cytokines, and effector cells (Bradley et al., 1991), is believed to play a central role in the pathogenesis as well as in the clinical manifestations of asthma. Thus, a speculative inference suggests that additional antiinflammatory properties shown by a prospective antiasthmatic drug would potentially represent an added value for the management of such a multifactorial condition (Roquet et al., 1997).