期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 10, 页码 2166-2170出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.03.060
关键词
Type 2 diabetes; PTP1B inhibitors; Phosphotyrosine mimics; Arylethenesulfonic acid esters
Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLogP = 9.73, P-app = 9.6 x 10(-6) cm/s; IC50 = 140, 1290 and 920 nM on PTP1B, TCPTP and SHP2, respectively). Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B. (C) 2017 Published by Elsevier Ltd.
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