Inhibition of Tumor Necrosis Factor-α (TNF-α) Production and Arthritis in the Rat by GW3333, a Dual Inhibitor of TNF-α-Converting Enzyme and Matrix Metalloproteinases

摘要: Tumor necrosis factor-α (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing mature to be secreted into extracellular space. GW3333, a dual inhibitor TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody evaluate importance soluble TNF MMPs in rat models arthritis. Oral administration GW3333 completely blocked increases plasma after LPS for up 12 h. In model wherein intrapleural zymosan injection causes increase pleural cavity, inhibited cavity Under these dosing conditions, levels unbound were at least 50-fold above IC50values inhibition individual vitro. bacterial peptidoglycan polysaccharide polymers reactivate local arthritis response ankle, neutralizing ankle swelling over 3-day reactivation period. administered b.i.d. same period also swelling, highest dose 80 mg/kg being slightly less active than antibody. 21-day adjuvant model, did not inhibit or joint destruction, as assessed by histology radiology. however, showed both destruction. conclusion, is first sufficient duration action chronically rat. The efficacy suggests that inhibitors may prove therapeutic antiarthritics.