Antiinflammatory benzimidazole derivative with inhibitory effects on neutrophil function.
5-Methyl-2,2,2-trifluoroethylsulfonyl-1H-benzimidazole (BI-L-45 XX) inhibits both neutrophil enzyme release and chemotaxis in vitro and also inhibits chemotaxis in vivo. BI-L-45 XX has an IC50 between 16 microM and 25 microM in inhibiting lysosomal enzyme release from human peripheral blood neutrophils. In a Boyden chamber experiment, BI-L-45 XX inhibited migration in response to fMLP with an IC50 of 5 microM. When given orally to passively sensitized rats at doses of 0.1 to 1.0 mg/kg, it inhibited migration of neutrophils to the pleural cavity in response to an antigen (ovalbumin) challenge. BI-L-45 XX also shows activity in the developing adjuvant arthritis model, with an ED50 of 45 mg/kg, while exhibiting no significant inhibition of cyclooxygenase in a human platelet assay. This suggests the possibility that its antiinflammatory activity may be in part mediated by its effect on neutrophil function.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
E S
ES
Lazer
P R
PR
Farina
J T
JT
Oliver
G J
GJ
Possanza
M R
MR
Matteo
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D004798:Enzymes; C054341:BI-L 45XX