期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 17, 页码 7783-7800出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00041
关键词
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资金
- Oklahoma Center for the Advancement of Science and Technology
- National Institutes of Health [5P20GM103636]
- Korea Institute of Science and Technology Institutional Program [2Z04690]
- National Research Council of Science Technology [CRC-15-04-KIST]
Pancreatic insulin-producing beta-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of beta-cell dysfunction and death. In diabetes, a major cause for the decline in beta-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of beta-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects beta-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 mu M. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet beta-cells. We showed that 9c protects beta-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.
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