MK-287

Leukotrienes (LTs) and platelet-activating factor (PAF) are important mediators of inflammation and allergy. LDP-392, a novel dual PAF receptor antagonist and 5-lipoxygenase (5-LO) inhibitor, has been identified. LDP-392 is 17.9-fold more potent than zileuton (5-LO inhibitor) in the RBL cytosolic 5-LO assay, and equally potent as MK 287 (PAF receptor antagonist) in the human platelet PAF receptor binding assay. The in vivo dual activities of LDP-392 were confirmed by measuring the inhibition of ex vivo LTB(4)production in rats and PAF-induced hemoconcentration in mice. Intravenous administration of LDP-392 demonstrated greater inhibition than zileuton, BN 50739 or MK 287 on arachidonic acid-induced ear edema and protected mice from LPS-induced lethality. Topical administration of LDP-392, in a dose-dependent manner, inhibited TPA-induced ear edema in mice and UVB-induced erythema in guinea-pigs. These data suggest that LDP-392, as a dual PAF receptor antagonist and 5-LO inhibitor, may be of greater clinical effectiveness.

ABT-299 is a water-soluble prodrug that is converted rapidly in vivo to A-85783, a highly potent, specific platelet-activating factor (PAF) antagonist.The K_i for inhibiting PAF binding to rabbit and human platelet membranes was 3.9 and 0.3 nM, resp.The inhibition was selective and reversible and was correlated with antagonism of PAF-mediated cellular responses (Ca²⁺ mobilization, priming of superoxide generation, and platelet aggregation and degranulation).The in vivo generation of A-85783 from ABT-299 led to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension and edema) and PAF-induced lethality.When administered i.v., the potency (ED₅₀) of ABT-299 for inhibiting PAF responses was 6-10 μg/kg in the rat and mouse and 100 μg/kg in the guinea pig.A dose of 100 μg/kg in the rat provided >60% protection for 8-16 h against cutaneous and systemic PAF challenge.This duration was also evidenced by ex vivo inhibition of platelet aggregation in guinea pigs and sheep.In addition to being active parenterally, ABT-299 exhibited oral activity in the rat and mouse (ED₅₀ = 100 μg/kg in both species).Pharmacokinetic studies in the rat revealed that ABT-299 was converted rapidly to A-85783 which, in turn, was metabolized to the corresponding pyridine-N-oxide and sulfoxide metabolites.These metabolites exhibited potency in vitro and in vivo and thus may contribute to the activity observed after administration of ABT-299.