THE EFFECTS OF FLUOROMETHYL KETONE INHIBITORS OF CATHEPSIN-B ON ADJUVANT-INDUCED ARTHRITIS

Peptidyl fluoromethyl ketones with the structure carbobenzoxy (Z)-L-ph enylalanine-L-alanine-CH2F (MDL 201,053), and its diastereomer Z-L-phe nylalanine-D-alanine-CH2F (MDL 201,117), were synthesized and evaluate d in vitro for inhibition of purified human cathepsin B. MDL 201,053 w as shown to be a potent inhibitor of cathepsin B activity, whereas MDL 201,117 was more than 100-fold less active. In rats with adjuvant ind uced arthritis, oral administration of MDL 201,053 (13 or 34 mg/kg/day ), but not MDL, 201,117 (28 mg/kg/day), significantly decreased the se verity of gross clinical arthritis and reduced histologically graded a rticular cartilage and bone destruction by 76 to 100%. Quantitative im age analysis of radiographs indicated that MDL 201,053 treatment signi ficantly reduced bone density changes and inhibited focal bone erosion that normally occur during the course of adjuvant disease. MDL 201,11 7 had no significant effect on cartilage or bone destruction by any of the evaluation methods used. The effects of MDL 201,053 treatment wer e dose dependent and treatment was at least partially effective when i nitiated after the onset of disease. Our studies suggest that inhibito rs of cathepsin B may be useful for the treatment of chronic inflammat ory joint disease.