1.
TNF-alpha converting enzyme (TACE) and
matrix metalloproteinases (
MMPs) are believed to play a role in various airway inflammatory disorders. Therefore we have tested the effect of two new inhibitors of TACE/
MMPs (PKF242-484, PKF241-466) in models of airway
inflammation. 2.
PKF242-484 and
PKF241-466 inhibited purified MMP-1, -2, -3, -9, -13 and rat
collagenase at low nanomolar range. Both compounds inhibited the
TNF-alpha release from activated human peripheral blood mononuclear cells with IC(50) values of 56+/-28 and 141+/-100 nM, respectively and had no significant effect on the activation of other human leukocytes, as neither neutrophils and eosinophils oxidative burst nor proliferation or
cytokines production by T cells were inhibited in vitro. 3.
PKF242-484 and
PKF241-466 had beneficial effects in two different murine models of acute
lung inflammation in vivo. The influx of neutrophils and lymphocytes into the airways was reduced 3 and 24 h after intranasal LPS challenge. This was accompanied by reduced levels of
myeloperoxidase and
elastase activities in the bronchoalveolar lavage. Furthermore, a complete inhibition of
TNF-alpha release into the airways was observed. In addition,
PKF242-484 effectively reduced the influx of neutrophils, eosinophils and lymphocytes in a model of acute allergic
lung inflammation. 4.
PKF242-484 and
PKF241-466 are two novel and potent dual inhibitors of TACE and
MMPs, which show activity in in vivo models of
lung inflammation. Such compounds could have beneficial effects in airway inflammatory conditions such as
asthma and
chronic obstructive pulmonary disease.