title: Y-shaped bis-arylethenesulfonic acid esters: Potential potent and membrane permeable protein tyrosine phosphatase 1B inhibitors.
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 (compound 7p, CLogP=9.73, Papp=9.6×10-6cm/s; IC50=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.
authors.affiliation: 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.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Xie
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China; Viva Biotech (Shanghai) Limited, Shanghai 201203, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Wenlu
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Faqin
authors.initials: F
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Celine
authors.initials: C
authors.lastname: Lam
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: dshxie@sjtu.edu.cn.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xie
authors.affiliation: China State Institute of Pharmaceutical Industry, Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, PR China. Electronic address: li.jianqi@sipi.com.cn.
authors.forename: Jianqi
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China. Electronic address: leifu@sjtu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004952:Esters / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D008051:Lipid Bilayers; D013451:Sulfonic Acids; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Arylethenesulfonic acid esters; PTP1B inhibitors; Phosphotyrosine mimics; Type 2 diabetes