ANTIARTHRITIC ACTIVITY OF HYDROXAMIC ACID-BASED PSEUDOPEPTIDE INHIBITORS OF MATRIX METALLOPROTEINASES AND TNF-ALPHA PROCESSING

Objective and Design: The effects of two hydroxamate inhibitors of met alloproteinase and tumor necrosis factor alpha (TNF alpha) processing on endotoxin-induced plasma TNF alpha and arthritic lesions in adjuvan t-induced arthritic (AA) rats were determined. Material and Treatment: BB-1101 and BE-1433 were administered orally twice daily to AA Lewis rats with an established disease (days 13 to 22). AA rats (day 16) or normal rats were injected with bacterial endotoxin and plasma levels o f TNF alpha were also determined. Methods: Hindpaw swelling was measur ed plethysmogra phically. Bone degradation was determined by radiograp hy and bone mineral densitometry. TNF alpha was quantified using a san dwich ELISA. Results: The hydroxamic-acid pseudopeptides inhibited pla sma TNF alpha levels in vivo and significantly reduced swelling and bo ne degradation of the tibiotarsal joints of AA rats in the range of 10 -50 mg/kg given orally (p < 0.01 by Student's t-test). Conclusions: Th us, these novel compounds offer a new disease-modifying therapy for ar thritis and the results also suggest that inhibition of TNF alpha prod uction may contribute, at least in part, to their anti-arthritic activ ity.