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Human leukocyte
elastase (HLE) is a proteinase capable of degrading a variety of proteins.
Under normal circumstances, natural inhibitors control the proteolytic
activity of HLE. However, an imbalance between elastase and these endogenous
inhibitors may result in several pathophysiological states such as chronic
obstructive pulmonary disease, asthma, emphysema, cystic fibrosis and chronic
inflammatory diseases. It is anticipated that an orally active HLE inhibitor
could be useful for the treatment of these diseases. Despite the
therapeutic implications of elastase inhibitors the drug development community
has so far failed to make major advances in the development of this
therapeutic class. Aventis have developeda formulation of alpha-1 protease
inhibitor, an endogenous protease inhibitor. Dyax are developing a similar
molecule. With regards to small molecule inhibitors, most advanced is Ono’s
Sivelestat (ONO-5046) which is a neutrophil elastase inhibitor, launched in
2002 for the treatment of acute lung injury caused by systemic inflammatory
response syndrome (SIRS). This molecule is in earlier stage development for
idiopathic pulmonary fibrosis (IPF) and chronic airway infection. Both Roche
and Dainippon have also recently advanced inhibitors into phase I trials for
the treatment of lung conditions. One of the most
recent elastase inhibitors to have been reported is Sanofi-Synthelabo’s
SSR69071. We introduced this molecule in the previous edition of
TherapeuticAdvances describing its efficacy in a model of coronary
ischemia and reperfusion. SSR69071 is nanomolar inhibitor of human, rat, mouse
and rabbit elastases. Oral treatment of mice with SSR69071 inhibits HLE
activity measured in recovered bronchoalveolar lavage fluid from mice, and
potently decreases acute lung hemorrhage induced by HLE (ED50=2.8 mg/kg po).
Furthermore, SSR69071 prevents carrageenan and HLE-induced paw edema in rats
after oral administration. In addition to previously reported cardiovascular efficacy, SSR69071 may also represent an excellent candidate for the treatment of inflammatory disease in particular, because of its good penetration in respiratory tissues, diseases characterized by airway inflammation. Entry date Adapted from Kapui et al, J Pharmacol Exp Ther 2003 Feb 11; [epub ahead of print]
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