期刊
BIOORGANIC CHEMISTRY
卷 92, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103273
关键词
PTP1B Inhibitors; Selectivity; 2-Ethoxy-4-(methoxymethyl)benzamide; Type 2 diabetes
资金
- Medicine and Engineering interdisciplinary Research Fund of Shanghai Jiao Tong University [YG2015QN03, YG2014MS10, YG2017MS77]
- National Natural Science Foundation of China [81202397]
- Shanghai Natural Science Fund [12ZR1415400]
Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the bioisosteric principle were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC50 = 0.07 mu M), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (P-app = 2.41 x 10(-6) cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.
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