PHARMACOLOGY OF ABT-491, A HIGHLY POTENT PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONIST

ABT-491 ridin-1-yl)methyl]benzoyl]-1H-indole-1-carboxamide hydrochlori de) is a novel PAF (platelet-activating factor) receptor antagonist wi th a K-i for inhibiting PAF binding to human platelets of 0.6 nM. Bind ing kinetics of ABT-491 to the PAF receptor is consistent with a relat ively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagon ism of PAF-mediated cellular responses (Ca2+ mobilization, priming, an d degranulation). Administration of ABT-491 in vivo leads to potent in hibition of PAF-induced inflammatory responses (increased vascular per meability, hypotension, and edema) and PAF-induced lethality. Oral pot ency (ED50) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-p ig. When administered intravenously in these species, ABT-491 exhibite d ED50 values between 0.005 and 0.016 mg/kg. An oral dose of 0.5 mg/kg in rat provided > 50% protection for 8 h against cutaneous PAF challe nge. ABT-491 administered orally was also effective in inhibiting lipo polysaccharide-induced hypotension (ED50 = 0.04 mg/kg), gastrointestin al damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs . 57% survival). The potency of this novel antagonist suggests that AB T-491 will be useful in the treatment of PAF-mediated diseases. (C) 19 97 Elsevier Science B.V.