Trpm2-specific inhibitors

A - Human Necessities – 61 – K

Patent

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A61K 31/70 (2006.01)

Patent

CA 2637006

The present invention relates to methods and compositions for modulating ADPR- mediated migratory activity of cells through regulation of the TRPM2 cation channel. Such methods and compositions may be used for the treatment of disorders including, but not limited to, inflammation, ischemia, atherosclerosis, asthma, autoimmune disease, diabetes, arthritis, allergies, and transplant rejection. Such cells include, for example, neutrophils, lymphocytes, eosinophils, macrophages, monocytes and dendritic cells. The invention further relates to specific inhibition of TRPM2 by blocking the activity of ADPR. The invention also relates to drug screening assays designed to identify compounds that regulate TRPM2 and thereby also function to modulate ADPR-mediated cell migration. The invention is based on the discovery that, 8Br-ADPR, which specifically inhibits activation of TRPM2, acts to inhibit ADPR-mediated cell migration.

La présente invention concerne des procédés et des compositions servant à moduler l'activité de migration liée à l'ADPR de cellules grâce à la régulation des canaux cationiques TRPM2. De tels procédés et de telles compositions peuvent être utilisés pour le traitement de troubles dont, sans y être limités, une inflammation, une ischémie, l'athérosclérose, l'asthme, une maladie auto-immune, le diabète, l'arthrite, des allergies et le rejet de greffe. De telles cellules comprennent, par exemple, des neutrophiles, des lymphocytes, des éosinophiles, des macrophages, des monocytes et des cellules dendritiques. L'invention concerne en outre l'inhibition spécifique des TRPM2 en bloquant l'activité de l'ADPR. L'invention concerne également des essais de criblage de médicaments conçus pour identifier des composés qui régulent les TRPM2 et de cette manière servent également à moduler la migration cellulaire liée à l'ADPR. L'invention est basée sur la découverte que le 8Br-ADPR, lequel inhibe spécifiquement l'activation des TRPM2, a pour effet d'inhiber la migration cellulaire liée à l'ADPR.

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