Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases

Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the prec ursor form of TNF, allowing the mature form to be secreted into the extrace llular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinase s (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h . In a model wherein intrapleural zymosan injection causes an increase in T NF in the pleural cavity, GW3333 completely inhibited the increase in TNF i n the pleural cavity for 12 h. Under these dosing conditions, the plasma le vels of unbound GW3333 were at least 50-fold above the IC50 values for inhi bition of individual MMPs in vitro. In a model wherein bacteria] peptidogly can polysaccharide polymers reactivate a local arthritis response in the an kle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the sa me period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, ho wever, showed inhibition of both ankle swelling and joint destruction. In c onclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 su ggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.