Preclinical pharmacology of pranlukast

Cysteinyl leukotrienes (cysLTs) exert potent biological actions through their specific receptors. They induce pathophysiological responses such as potent bronchoconstriction, mucus secretion, mucosal oedema and eosinophil infiltration. The regulation of these responses may provide a novel therapeutic approach in the treatment of allergic and inflammatory diseases. We have developed a cysLT receptor antagonist, pranlukast as one of cysLT modifiers. Preclinical pharmacology studies demonstrate that pranlukast is a potent, selective and orally active antagonist of cysLT 1 receptor. Pranlukast competed with [ 3 H]cysLTs for binding to cysLT receptors on guinea‐pig lung and nasal mucosa membranes and inhibited LTD 4 ‐induced calcium mobilization through human cysLT 1 receptors expressed on CHO cells. Oral administration of pranlukast inhibited cysLTs‐induced symptomatology in guinea‐pigs. In sensitized guinea‐pig models of asthma, pranlukast inhibited antigen‐induced early and late phase bronchoconstrictions, airway hyperresponsiveness, microvascular leakage and eosinophil infiltration into airways. Furthermore, in sensitized Brown Norway rats, pranlukast suppressed airway smooth muscle proliferation and collagen deposition characteristic of airway wall remodelling. In guinea‐pig models of allergic rhinitis, pranlukast potently blocked a biphasic nasal obstruction resistant to antihistamines, sneezing and nasal secretion induced by nasal hyperresponsiveness, suggesting the prominent efficacy of pranlukast in allergic rhinitis. From these pharmacological properties of pranlukast, it is suggested that cysLT 1 receptor antagonists are useful and beneficial as a new class of antiallergic and anti‐inflammatory agents in the treatment and management of asthma and allergic rhinitis.