Discovery of N-(2-(Benzylamino)-2-oxoethyl)benzamide analogs as a novel scaffold of pancreatic β-cell protective agents against endoplasmic reticulum stress.
Discovery of N-(2-(Benzylamino)-2-oxoethyl)benzamide analogs as a novel scaffold of pancreatic β-cell protective agents against endoplasmic reticulum stress.
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发现N-(2-(苄氨基)-2-氧代乙基)苯甲酰胺类似物作为抗内质网应激的胰腺β细胞保护剂的新型支架。
DOI：
10.1111/cbdd.13650
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发表时间：
2020
影响因子：
3
通讯作者：
Wang,Weidong
中科院分区：
文献类型：
--
作者：
Eeda,Venkateswararao;Herlea-Pana,Oana;Lim,Hui-Ying;Wang,Weidong
内质网应激诱导的胰腺β细胞功能障碍和死亡在糖尿病的发生发展中起重要作用。1,2,3 -三唑衍生物是迄今为止已确定的保护β细胞免受内质网应激的少数结构之一。然而，该化合物具有较窄的活性范围和有限的水溶性。为了克服这些问题，我们设计并合成了一种新的支架，其中三唑药效团被甘氨酸样氨基酸取代。结构-活性关系研究表明，该支架具有aN‐（2‐（苄基氨基）‐2‐氧乙基）苯酰胺类似物wo5m，具有β‐细胞保护活性，对内质网应激具有显著提高的效力（最大活性为100%，ec50为0.1±0.01µm）和水溶性。因此，这种新型β细胞保护支架的鉴定为糖尿病的治疗提供了一种新的有希望的模式。
Endoplasmic reticulum (ER) stress‐induced pancreatic β‐cell dysfunction and death play important roles in the development of diabetes. The 1,2,3‐triazole derivative1is one of only a few structures that have thus far been identified that protect β 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 aN‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analogWO5mthat possesses β‐cell protective activity against ER stress with much improved potency (maximal activity at 100% with EC50at 0.1 ± 0.01 µm) and water solubility. Identification of this novel β‐cell protective scaffold thus provides a new promising modality for the treatment of diabetes.