Hydroxybenzamide derivatives protect pancreatic β cell by suppressing unfolded protein response activation.

Endoplasmic reticulum (ER) stress-induced Pancreatic β-cell dysfunction and death plays important roles in the development of diabetes. The 1,2,3-triazole derivative 1 is one of only a few structures that have thus far been identified that protect β cells against ER stress, but it is limited for its narrow activity range. In this study, we designed and synthesized a series of hydroxybenzamide (HBA) derivatives in which the triazole pharmacophore was substituted with an amide linker. Structure-activity relationship studies identified WO3i (3-hydroxy-N-(4-[trifluoromethyl]benzyl)benzamide) that possesses β-cell protective activity against ER stress at a 100% maximal activity with EC at 0.19 μM). We showed that WO3i suppresses the expression of CHOP, a key mediator of ER stress-induced apoptosis, and the activation of apoptotic genes. Mechanistically, we further showed that WO3i suppresses the ER stress-induced activation of all three pathways of unfolded protein response-ATF6, IRE1α, and PERK. Identification of this novel β-cell-protective scaffold thus provides a new promising modality for the potential for drug development for the treatment of diabetes.