PHARMACOLOGICAL ACTIVITY OF THE 2ND-GENERATION LEUKOTRIENE B-4 RECEPTOR ANTAGONIST, SC-53228 - EFFECTS ON ACUTE COLONIC INFLAMMATION AND HEPATIC-FUNCTION IN RODENTS

Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes ulcerative colitis and Crohn's disease. Leukotriene B-4 is thought to be a prominent proinflammatory mediator in these diseases, in that leukotriene B-4 levels are increased in the colonic mucosa of inflammatory bowel disease patients and there is increased polymorphonuclear leukocyte infiltration of these tissues. SC-53228 {(+)-(S)-7-[3-[2(-cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid}, a second generation LTB(4) receptor antagonist, was evaluated for therapeutic efficacy in a rodent model of acute colonic inflammation induced by short chain organic acids, as well as for effects on rodent liver. When given intracolonically to mice, SC-53228 inhibited neutrophil infiltration, assessed by myeloperoxidase (MPG) levels, with an ED(50) value of 9 +/- 1.2 mg/kg. When given by gavage, SC-53228 inhibited neutrophil influx in colitic mice with an ED(50) value of 30 mg/kg. These results were also confirmed histologically. Furthermore, high dose oral SC-53228 treatment had no effect on liver cytochrome P-450 content, fatty acyl CoA oxidase or liver weight in rats and mice. Together, these data suggest that SC-53228 may be efficacious orally and locally, as well as safe for use in trials for the medical management of IBD.