Pharmacological activity of the second generation leukotriene B4 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 B4 is thought to be a prominent proinflammatory mediator in these diseases, in that leukotriene B4 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 LTB4 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 (MPO) levels, with an ED50 value of 9 +/- 1.2 mg/kg. When given by gavage, SC-53228 inhibited neutrophil influx in colitic mice with an ED50 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.
Fretland
D J
DJ
Searle Research and Development, Skokie, Illinois 60077, USA.
Anglin
C P
CP
Widomski
D
D
Baron
D A
DA
Maziasz
T
T
Smith
P F
PF
D042962:Acyl-CoA Oxidase; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D003092:Colitis / Q000201:enzymology / Q000473:pathology*; D003106:Colon / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D001549:Benzamides; D001578:Benzopyrans; D018102:Receptors, Leukotriene B4; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D009195:Peroxidase; D042962:Acyl-CoA Oxidase; D015248:Gemfibrozil; D010634:Phenobarbital