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Eur J Med Chem. 2019 Feb 15;164:408-422. doi: 10.1016/j.ejmech.2018.12.032. Epub 2018 Dec 14.

Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors.

Author information

1
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), 800 Dongchuan Road, Shanghai 200240, China.
2
Shanghai Ambiopharm, Inc., 388 Chugong Rd., Shanghai Chemical Industry Park, Shanghai 201424, China.
3
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), 800 Dongchuan Road, Shanghai 200240, China; Viva Biotech (Shanghai) Limited, Shanghai 201203, China.
4
School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai 200240, China.
5
ChemPartner Co., Ltd., 998 Halei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203, China. Electronic address: dshxie@chempartner.com.
6
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), 800 Dongchuan Road, Shanghai 200240, China. Electronic address: leifu@sjtu.edu.cn.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC50 = 120, 1940 and 2670 nM against PTP1B, TCPTP and SHP2 respectively, and Papp = 1.74 × 10-6 cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.

KEYWORDS:

PTP1B inhibitors; Pyrrolidine bisarylethenesulfonic acid esters; Selectivity; Type 2 diabetes

PMID:
30611982
DOI:
10.1016/j.ejmech.2018.12.032
[Indexed for MEDLINE]

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