Development of new scaffolds as reversible tissue transglutaminase inhibitors, with improved potency or resistance to glutathione addition

作者：Apperley Kim Y P; Roy Isabelle; Saucier Vincent; Brunet Filion Nicholas; Piscopo Sara Pier; Pardin Christophe; De Francesco Elise; Hao Catherine; Keillor Jeffrey W^*

来源：Medchemcomm, 2017, 8(2): 338-345.

DOI：10.1039/c6md00565a

Previous studies within our group have yielded a class of cinnamoyl-based competitive reversible inhibitors for tissue transglutaminase (TG2), with K-i values as low as 1.0 mu M (compound CP4d). However, due to the electrophilic nature of their alkene moiety, this class of inhibitors is susceptible to nucleophilic attack by glutathione, a key element in cellular metabolism and toxicity response. To address this issue, we made several modifications to the inhibitor scaffold, ultimately showing that a bis(triazole) scaffold increased resistance to nucleophilic attack, with compound 27d being the most potent (K-i = 10 mu M). In the process of reducing reactivity, we also prepared a new class of inhibitors, replacing the alkene of CP4d with an alkyne, leading to a significant increase in potency for compound 22b (K-i = 420 nM).

• 出版日期2017