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Vol. 298, Issue 3, 900-908, September 2001
(TNF-) Production and
Arthritis in the Rat by GW3333, a Dual Inhibitor
of TNF--Converting Enzyme and Matrix Metalloproteinases
Glaxo Wellcome Inc., Research Triangle Park, North Carolina
(J.G.C., R.C.A., B.B., D.M.B., V.B., T.A.B., R.C.C., M.A.L., D.L.D.,
B.H., K.H., P.L., M.Mi., M.Mo., H.P., M.H.R., T.T., P.W.S., J.S.,
S.A.S., J.W., J.D.B.); and Department of Radiology, University of North
Carolina School of Medicine, Chapel Hill, North Carolina (R.L.C.)
Tumor necrosis factor-
(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 IC50
values 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.
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