Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis.
Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB4 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 LTB4 in such diseases has not yet been defined but in this paper we provide direct evidence that LTB4 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 LTB4 receptor antagonist that inhibits LTB4 binding to human neutrophil membranes with an IC50 of 3.7 nM and inhibits LTB4-induced chemotaxis of these cells with an IC50 of 5.2 nM. CP-105,696 inhibits LTB4-induced neutrophil influx in mouse skin when administered orally with an ED50 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 LTB4 receptor antagonists may be effective therapeutic agents for the treatment of RA.
Griffiths
R J
RJ
Central Research Division, Pfizer Inc., Groton, CT 06340.
Pettipher
E R
ER
Koch
K
K
Farrell
C A
CA
Breslow
R
R
Conklyn
M J
MJ
Smith
M A
MA
Hackman
B C
BC
Wimberly
D J
DJ
Milici
A J
AJ
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology*; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D002264:Carboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007596:Joints / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D001578:Benzopyrans; D002264:Carboxylic Acids; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C089698:CP 105696