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

Abstract

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.

• Authors: C Qian, S B Hwang, L Libertine-Garahan, J B Eckman, X Cai, R T Scannell, C G Yeh
• Journal: Pharmacological research (Pharmacol Res) Vol. 44 Issue 3 Pg. 213-20 (Sep 2001) ISSN: 1043-6618 [Print] Netherlands
• PMID: 11529688 (Publication Type: Journal Article)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Furans
• Lipoxygenase Inhibitors
• Platelet Activating Factor
• Platelet Membrane Glycoproteins
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• platelet activating factor receptor
• CMI 392
• Urea
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Arachidonate 5-Lipoxygenase (metabolism)
• Dose-Response Relationship, Drug
• Edema (drug therapy)
• Erythema (drug therapy)
• Female
• Furans (pharmacology)
• Guinea Pigs
• Humans
• Lipoxygenase Inhibitors (pharmacology, therapeutic use)
• Mice
• Platelet Activating Factor (metabolism)
• Platelet Membrane Glycoproteins (antagonists & inhibitors, metabolism)
• Rats
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• Urea (analogs & derivatives, pharmacology)