Y-shaped bis-arylethenesulfonic acid esters: Potential potent and membrane permeable protein tyrosine phosphatase 1B inhibitors. Issue 10 (15th May 2017)

• Record Type: Journal Article
• Authors: Yang, Fengzhi; Xie, Fangzhou; Zhang, Ying; Xia, Yu; Liu, Wenlu; Jiang, Faqin; Lam, Celine; Qiao, Yixue; Xie, Dongsheng; Li, Jianqi; Fu, Lei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 10(2017)
• Page Start: 2166
• Page End: 2170
• Publication Date: 2017-05-15
• Subjects: Type 2 diabetes -- PTP1B inhibitors -- Phosphotyrosine mimics -- Arylethenesulfonic acid esters; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.03.060
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: The optimization of aryl ethenesulfonic acid esters for PTP1B inhibition. Highlights: A new class of nonionic PTP1B inhibitors was found. They are highly potent and moderately selective. They have great potential in penetrating cellular membranes. They interact with multiple secondary binding sites of PTP1B. Abstract: 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 (compound7p, CLog P = 9.73, Papp = 9.6 × 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.