CMI-392

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.

The present paper describes the synthesis of the title compound I, (±)-trans-2-{3-methoxy-4-[2-(4-chlorophenylthio)ethoxy]-5-[(N-hydroxy-N-methylureidyl)methyl]phenyl}-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, applying green methodologies, from com. available 5-iodovanillin and 3,4,5-(MeO)₃C₆H₂CHO as starting materials.Compound I and its intermediates were screened against bacterial strains, i.e. Gram pos. (S. aureus, B. sphaericus, B. megaterium) and Gram neg. (P. putida, E. aerogenes) strains.Compound I displayed excellent antibacterial activity.