Pentoxifylline, pioglitazone and metformin are inhibitors of...

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A61K 31/00 (2006.01) A61K 31/155 (2006.01) A61K 31/4439 (2006.01) A61K 31/522 (2006.01)

Patent

CA 2371391

Pentoxifylline, pioglitazone and metformin have been found to inhibit the nonenzymatic glycation of proteins which often results in formation of advanced glycation endproducts and crosslinks. The nonenzymatic glycation and crosslinking of proteins is a part of the aging process with the glycation endproducts and crosslinking of long-lived proteins increasing with age. This process is increased at elevated concentrations of reducing sugars in the blood and in the intracellular environment such as occurs with diabetes. The structural and functional integrity of the affected molecules become perturbed by these modifications and can result in severe consequences. The compounds of the present invention can be used to inhibit this process of nonenzymatic glycation and therefore to inhibit some of the ill effects caused by diabetes or by aging. The compounds are also useful for preventing premature aging, rheumatoid arthritis, Alzheimer's disease, uremia, neurotoxicity, atherosclerosis ans spoilage of proteins in food and can prevent discoloration of teeth.

On a découvert que la pentoxifylline, le pioglitazone et la metformine permettaient d'inhiber la glycation non enzymatique de protéines, résultant souvent de la formation de produits terminaux de glycation avancée et de liaisons réticulées. La glycation non enzymatique et la réticulation des protéines font partie du processus de vieillissement associé audits produits terminaux de glycation et à la réticulation des protéines longue durée augmentant avec âge. Ce processus augmente à des concentrations élevées de sucre de réduction dans le sang et dans l'environnement intracellulaire tel qu'il se présente dans les diabètes. L'intégrité structurelle et fonctionnelle des molécules affectées se trouve perturbée par ces modifications, ce qui peut entraîner des conséquences sévères. Les composés de l'invention peuvent être utilisés pour inhiber ledit processus de glycation non enzymatique, et donc inhiber certains effets néfastes provoqués par les diabètes ou par le vieillissement. Ces composés sont également utiles pour empêcher le vieillissement prématuré, la polyarthrite rhumatoïde, la maladie d'Alzheimer, l'urémie, la neurotoxicité, l'athérosclérose, la dégradation des protéines dans la nourriture, et la décoloration des dents.

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