Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist

ABT-491 (4-ethynyl- N , N -dimethyl-3-[3-fluoro-4-[(2-methyl-1 H -imidazo-[4,5- c ]pyridin-1-yl)methyl]benzoyl]-1 H -indole-1-carboxamide hydrochloride) is a novel PAF (platelet-activating factor) receptor antagonist with a K i for inhibiting PAF binding to human platelets of 0.6 nM. Binding kinetics of ABT-491 to the PAF receptor is consistent with a relatively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagonism of PAF-mediated cellular responses (Ca 2+ mobilization, priming, and degranulation). Administration of ABT-491 in vivo leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension, and edema) and PAF-induced lethality. Oral potency (ED 50 ) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-pig. When administered intravenously in these species, ABT-491 exhibited ED 50 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 challenge. ABT-491 administered orally was also effective in inhibiting lipopolysaccharide-induced hypotension (ED 50 =0.04 mg/kg), gastrointestinal damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs. 57% survival). The potency of this novel antagonist suggests that ABT-491 will be useful in the treatment of PAF-mediated diseases. © 1997 Elsevier Science B.V.