Discovery of N-(2-(Benzylamino)-2-oxoethyl)benzamide analogs as a novel scaffold of pancreatic ß-cell protective agents against endoplasmic reticulum stress.
Chem Biol Drug Des
; 95(3): 388-393, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31755655
ABSTRACT
Endoplasmic reticulum (ER) stress-induced pancreatic ß-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 ß 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 ß-cell protective activity against ER stress with much improved potency (maximal activity at 100% with EC50 at 0.1 ± 0.01 µm) and water solubility. Identification of this novel ß-cell protective scaffold thus provides a new promising modality for the treatment of diabetes.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article