PT  - JOURNAL ARTICLE
AU  - James G. Conway
AU  - Robert C. Andrews
AU  - Beth Beaudet
AU  - D. Mark Bickett
AU  - Virginia Boncek
AU  - Thomas A. Brodie
AU  - Richard L. Clark
AU  - R. Christian Crumrine
AU  - Michael A. Leenitzer
AU  - Darryl L. McDougald
AU  - Bajin Han
AU  - Kevin Hedeen
AU  - Peiyuan Lin
AU  - Marcos Milla
AU  - Marcia Moss
AU  - Heather Pink
AU  - Michael H. Rabinowitz
AU  - Timothy Tippin
AU  - Phillip W. Scates
AU  - Jeffrey Selph
AU  - Stephen A. Stimpson
AU  - Janet Warner
AU  - J. David Becherer
TI  - 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
DP  - 2001 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 900--908
VI  - 298
IP  - 3
4099  - http://jpet.aspetjournals.org/content/298/3/900.short
4100  - http://jpet.aspetjournals.org/content/298/3/900.full
SO  - J Pharmacol Exp Ther2001 Sep 01; 298
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