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| - Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 byDihydroisoxazoles
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| - Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various humandisorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibitionof TG2 should therefore enable further investigation of its role in physiology and disease and may lead toeffective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containingcompounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, wepresent definitive evidence that this class of compounds targets the active site of human TG2. Structure−activity relationship studies have provided insights into the structural prerequisites for selectivity and haveled to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazoleinhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was alsodeveloped. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2than its 5-(R) stereoisomer.
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