title: Peptidyl fluoromethyl ketones as inhibitors of cathepsin B. Implication for treatment of rheumatoid arthritis.
abstract: Peptidyl fluoromethyl ketones (FMKs), with the amino acid sequence Phe-Ala held constant but with variable N-terminal groups, were synthesized and tested for inhibition of the cysteine proteinase cathepsin B. The FMKs were effective in inhibiting cathepsin B activity in vitro. The inhibition was time dependent and was not reversed by dialysis, suggesting covalent modification of the enzyme. Cathepsin B activity present in livers and kidneys of rats treated with FMKs was reduced by 22-91% 4 hr after a single oral dose of 25 mg/kg. The FMKs inhibited the severity of inflammation and the extent of cartilage and bone damage in adjuvant-induced arthritis. These effects were seen during the late-stage of the disease with no effect on onset or incidence of disease. This is consistent with inhibition of protease-mediated damage. These FMKs or derivatives may be of clinical value in the treatment of arthritis.
authors.affiliation: Marion Merrell Dow Inc., Kansas City, MO 64137-1601.
authors.forename: N K
authors.initials: NK
authors.lastname: Ahmed
authors.forename: L A
authors.initials: LA
authors.lastname: Martin
authors.forename: L M
authors.initials: LM
authors.lastname: Watts
authors.forename: J
authors.initials: J
authors.lastname: Palmer
authors.forename: L
authors.initials: L
authors.lastname: Thornburg
authors.forename: J
authors.initials: J
authors.lastname: Prior
authors.forename: R E
authors.initials: RE
authors.lastname: Esser
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001835:Body Weight / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D007659:Ketones; C057383:MDL 201053; D002401:Cathepsin B