Discovery of a Benzamide Derivative That Protects Pancreatic β-Cells against Endoplasmic Reticulum Stress

Endoplasmic reticulum (ER) stress-mediated pancreatic insulin-producing beta-cell dysfunction and death are critical elements in the onset and progression of both type 1 and type 2 diabetes. Here, through cell-based high throughput screening we identified benzamide derivatives as a novel class of beta-cell protective agents against ER stress-induced dysfunction and death. Through structure activity relationship optimization, a 3-(N-piperidinyl)methylbenzamide derivative 13d markedly protects beta-cells against ER stress-induced dysfunction and death with near 100% maximum rescue activity and an EC50 of 0.032 mu M. Compound 13d alleviates ER stress in beta-cells by suppressing ER stress-mediated activation of all three branches of unfolded protein response (UPR) and apoptotic genes. Finally, we show that 13d significantly lowers blood glucose levels and increases concomitant beta-cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of beta-cell-protective small molecules against ER stress provides a new promising modality for the treatment of diabetes.