PROPERTIES OF ABT-299, A PRODRUG OF A-85783, A HIGHLY POTENT PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONIST

ABT-299 is an aqueous soluble prodrug that is converted rapidly in viv o to A-85783, a novel, highly potent, specific platelet activating fac tor (PAF) antagonist. The K-i for inhibiting PAF binding to rabbit pla telet membranes is 3.9 and 0.3 nM for human platelets. Inhibition is s elective and reversible and is correlated with functional antagonism o f PAF-mediated cellular responses (calcium mobilization, priming, of s uperoxide generation, aggregation and degranulation). The in vivo gene ration of A-85783 from ABT-299 leads to potent inhibition of PAF-induc ed inflammatory responses (increased vascular permeability, hypotensio n and edema) and PAF-induced lethality. When administered i.v. the pot ency (ED(50)) of ABT-299 for inhibiting PAF responses was between 6 to 10 mu g/kg in the rat and mouse and 100 mu g/kg in the guinea pig. A dose of 100 mu g/kg in the rat provided greater than 60% protection fo r 8 to 16 hr against cutaneous and systemic PAF challenge. This durati on was also evidenced by ex vivo inhibition of platelet aggregation in guinea pig and sheep. In addition to being active parenterally, ABT-2 99 exhibited p.o. activity in the rat and mouse (ED(50) = 100 mu g/kg in both species). Pharmacokinetic studies in the rat revealed that ABT -299 was converted rapidly to A-85783 and, in turn, metabolized to the corresponding pyridine-N-oxide and sulfoxide metabolites. These metab olites exhibited significant potency in vitro and in vivo and thus may contribute to the activity observed after administration of ABT-299.