3 years ago

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

Discovery of a Benzamide Derivative That Protects Pancreatic β-Cells against Endoplasmic Reticulum Stress
Hui-Ying Lim, Daleep Arora, Depeng Xu, Weidong Wang, Hongliang Duan, Yu Li
Endoplasmic reticulum (ER) stress-mediated pancreatic insulin-producing β-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 β-cell protective agents against ER stress-induced dysfunction and death. Through structure–activity relationship optimization, a 3-(N-piperidinyl)methylbenzamide derivative 13d markedly protects β-cells against ER stress-induced dysfunction and death with near 100% maximum rescue activity and an EC50 of 0.032 μM. Compound 13d alleviates ER stress in β-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 β-cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of β-cell-protective small molecules against ER stress provides a new promising modality for the treatment of diabetes.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00435

DOI: 10.1021/acs.jmedchem.7b00435

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