Discovery of N‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analogs as a Novel Scaffold of Pancreatic β‐cell Protective Agents against ER Stress

Endoplasmic reticulum (ER) stress-induced pancreatic beta-cell dysfunction and death play 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 beta cells against ER stress. However, this compound has narrow activity range and limited aqueous solubility. To overcome these, we designed and synthesized a new scaffold in which the triazole pharmacophore was substituted with a glycine-like amino acid. Structure-activity relationship studies on this scaffold identified a N-(2-(Benzylamino)-2-oxoethyl)benzamide analog WO5m that possesses beta-cell protective activity against ER stress with much improved potency (maximal activity at 100% with EC50 at 0.1 +/- 0.01 microm) and water solubility. Identification of this novel beta-cell protective scaffold thus provides a new promising modality for the treatment of diabetes.