RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 900
OP 908
VO 298
IS 3
A1 James G. Conway
A1 Robert C. Andrews
A1 Beth Beaudet
A1 D. Mark Bickett
A1 Virginia Boncek
A1 Thomas A. Brodie
A1 Richard L. Clark
A1 R. Christian Crumrine
A1 Michael A. Leenitzer
A1 Darryl L. McDougald
A1 Bajin Han
A1 Kevin Hedeen
A1 Peiyuan Lin
A1 Marcos Milla
A1 Marcia Moss
A1 Heather Pink
A1 Michael H. Rabinowitz
A1 Timothy Tippin
A1 Phillip W. Scates
A1 Jeffrey Selph
A1 Stephen A. Stimpson
A1 Janet Warner
A1 J. David Becherer
YR 2001
UL http://jpet.aspetjournals.org/content/298/3/900.abstract
AB Tumor necrosis factor-α (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (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 TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC50values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same 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, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics. The American Society for Pharmacology and Experimental Therapeutics