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.
Lazer
E S
ES
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
Farina
P R
PR
Oliver
J T
JT
Possanza
G J
GJ
Matteo
M R
MR
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