LEUKOTRIENE B-4 PLAYS A CRITICAL ROLE IN THE PROGRESSION OF COLLAGEN-INDUCED ARTHRITIS

Leukotriene B-4 (LTB(4)) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB(4) is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. The role of LTB(4) in such diseases has not yet been defined but in this paper we provide direct evidence that LTB(4) plays a critical role in a murine model of RA. CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl] cyclopentane carboxylic acid, is an LTB(4) receptor antagonist that inhibits LTB(4) binding to human neutrophil membranes with an IC50 of 3.7 nM and inhibits LTB(4)-induced chemotaxis of these cells with an IC50 of 5.2 nM. CP-105,696 inhibits LTB(4)-induced neutrophil influx in mouse skin when administered orally with an ED(50) of 4.2 mg/kg. CP-105,696 had a dramatic effect on both the clinical symptoms and histological changes of murine collagen-induced arthritis when administered at doses of 0.3-10 mg/kg. Inhibition was not associated with suppression of the humoral immune response to collagen and was equally effective if drug treatment was commenced just prior to the onset of arthritis or throughout the experiment. These results suggest that LTB(4) receptor antagonists may be effective therapeutic agents for the treatment of RA.