title: 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.affiliation: Millennium Pharmaceutical Inc., Cambridge, MA 02139, USA. cqian@mpi.com
authors.forename: C
authors.initials: C
authors.lastname: Qian
authors.forename: S B
authors.initials: SB
authors.lastname: Hwang
authors.forename: L
authors.initials: L
authors.lastname: Libertine-Garahan
authors.forename: J B
authors.initials: JB
authors.lastname: Eckman
authors.forename: X
authors.initials: X
authors.lastname: Cai
authors.forename: R T
authors.initials: RT
authors.lastname: Scannell
authors.forename: C G
authors.initials: CG
authors.lastname: Yeh
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D004890:Erythema / Q000188:drug therapy; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005663:Furans; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C112433:CMI 392; D014508:Urea; D001094:Arachidonate 5-Lipoxygenase