Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNFα processing

Abstract

Objective and Design: The effects of two hydroxamate inhibitors of metalloproteinase and tumor necrosis factor α (TNFα) processing on endotoxin-induced plasma TNFα and arthritic lesions in adjuvant-induced arthritic (AA) rats were determined.¶Material and Treatment: BB-1101 and BB-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 of TNFα were also determined.¶Methods: Hindpaw swelling was measured plethysmographically. Bone degradation was determined by radiography and bone mineral densitometry. TNFα was quantified using a sandwich ELISA.¶Results: The hydroxamic-acid pseudopeptides inhibited plasma TNFα levels in vivo and significantly reduced swelling and bone 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: Thus, these novel compounds offer a new disease-modifying therapy for arthritis and the results also suggest that inhibition of TNFα production may contribute, at least in part, to their anti-arthritic activity.