Anti-inflammatory activities of LDP-392, a dual PAF receptor antagonist and 5-lipoxygenase inhibitor

Leukotrienes (LTs) and platelet-activating factor (PAF) are important media tors of inflammation and allergy. LDP-392, a novel dual PAF receptor antago nist and 5-lipoxygenase (5-LO) inhibitor, has been identified. LDP-392 is 1 7.9-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 hum an platelet PAF receptor binding assay. The in vivo dual activities of LDP- 392 were confirmed by measuring the inhibition of ex vivo LTB4 production i n rats and PAF-induced hemoconcentration in mice. Intravenous administratio n of LDP-392 demonstrated greater inhibition than zileuton, BN 50739 or MK 287 on arachidonic acid-induced ear edema and protected mice from LPS-induc ed lethality. Topical administration of LDP-392, in a dose-dependent manner , inhibited TPA-induced ear edema in mice and UVB-induced erythema in guine a-pigs. These data suggest that LDP-392, as a dual PAF receptor antagonist and 5-LO inhibitor, may be of greater clinical effectiveness. (C) 2001 Acad emic Press.