Yang Fengzhi, Xie Fangzhou, Zhang Ying, Xia Yu, Liu Wenlu, Jiang Faqin, Lam Celine, Qiao Yixue, Xie Dongsheng, Li Jianqi, Fu Lei
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China; China State Institute of Pharmaceutical Industry, Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, PR China.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
Bioorg Med Chem Lett. 2017 May 15;27(10):2166-2170. doi: 10.1016/j.bmcl.2017.03.060. Epub 2017 Mar 23.
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=9.6×10cm/s; IC=140, 1290 and 920nM 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.
已知具有双阴离子部分的蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂表现出强大的抑制活性和良好的选择性，然而，它们无法穿透细胞膜。基于我们在抑制PTP1B方面发现的新药效基团以及PTP1B结合口袋的结构特征，设计并合成了一系列双芳基乙烯磺酸酯衍生物。这些新型分子，特别是Y形双芳基乙烯磺酸酯衍生物，表现出高PTP1B抑制活性、适度的选择性以及在穿透细胞膜方面的巨大潜力（化合物7p，CLogP = 9.73，通透系数P = 9.6×10cm/s；对PTP1B、TCPTP和SHP2的IC50分别为140、1290和920 nM）。对接模拟表明，这些Y形抑制剂除了与PTP1B的催化位点相互作用外，还可能与多个二级结合位点相互作用。
