RUPATADINE, A NEW POTENT, ORALLY-ACTIVE DUAL ANTAGONIST OF HISTAMINE AND PLATELET-ACTIVATING-FACTOR (PAF)

Rupatadine (UR-12592, inylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridin e) is a novel compound that inhibits both platelet-activating factor ( PAF) and histamine (H-1) effects through its interaction with specific receptors (K-i(app) values against [H-3]WEB-2086 binding to rabbit pl atelet membranes and [H-3]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 mu M, respectively). Rupatadine competit ively inhibited histamine-induced guinea pig ileum contraction (pA(2) = 9.29 +/- 0.06) without affecting contraction induced by ACh, seroton in or leukotriene D-4 (LTD(4)). It also competitively inhibited PAF-in duced platelet aggregation in washed rabbit platelets (WRP) (pA(2) = 6 .68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 mu M), while not affecting ADP- or arachidonic acid-induced platelet agg regation. Rupatadine blocked histamine- and PAF-induced effects in viv o, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respec tively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 mu g/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in m ice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endoto xin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v. ). Rupatadine's duration of action was long, as assessed by the histam ine- and PAF-induced increase in vascular permeability test in dogs (4 2 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor pro longed barbiturate-sleeping time in mice, which indicates a lack of se dative effects. Overall, rupatadine combines histamine and PAF antagon ist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadi ne's PAF antagonist effects were near those of WEB-2086. Rupatadine is therefore a good candidate for further development in the treatment o f allergic and inflammatory, conditions in which both PAF and histamin e are implicated.