Titre :
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In vitro profiling of calpain inhibitors as potential drug candidates for the treatment of Duchenne muscular dystrophy (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Briguet A ;
Courdier-Fruh I ;
Foster M ;
Erb M ;
Meier T ;
Lescop C ;
Siendt H ;
Herzner H ;
Henneboehle M ;
Weyermann P ;
von Sprecher A ;
Magyar J
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 295
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Langues:
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Anglais
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Mots-clés :
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colloque
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dystrophie musculaire de Duchenne
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in vitro
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inhibiteur de la calpaïne
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pharmacothérapie
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souris mdx
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Résumé :
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Communication n° 24 Calpain I and II are ubiquitous calcium-dependent cytosolic cystein proteases that are activated in dystrophin-deficient muscles. Inhibition of calpains by overexpression of its endogenous inhibitor calpastatin has been shown to reduce dystrophic symptoms in mdx-mice. Therefore calpain inhibiton is regarded as a treatment option for Duchenne muscular dystrophy (DMD). However to date there is no small-molecule calpain inhibitor approved that could be evaluated for treatment of DMD. Starting from known calpain inhibitor lead compounds such as the industry standard MDL28170, we have launched a lead optimization program to develop small-molecule calpain inhibitors for therapeutic application in DMD. In vitro profiling of over 800 compounds in cell-free and cellular calpain inhibition assays led to the characterization of calpain inhibitors with greatly improved potency compared to reference compounds. Moreover, testing of these calpain inhibitors against the 20S proteasome and cathepsin-B, two additional proteases potentially involved in muscle protein breakdown, revealed the existence of compound classes with different specificity profiles.
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