TY - JOUR
T1 - Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors
AU - Xie, Fangzhou
AU - Yang, Fengzhi
AU - Liang, Yaoyao
AU - Li, Liang
AU - Xia, Yu
AU - Jiang, Faqin
AU - Liu, Wenlu
AU - Qi, Yunyue
AU - Chowdhury, Sharmin Reza
AU - Xie, Dongsheng
AU - Fu, Lei
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2019/2/15
Y1 - 2019/2/15
N2 - 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.
AB - 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.
KW - PTP1B inhibitors
KW - Pyrrolidine bisarylethenesulfonic acid esters
KW - Selectivity
KW - Type 2 diabetes
UR - https://www.scopus.com/pages/publications/85059342148
U2 - 10.1016/j.ejmech.2018.12.032
DO - 10.1016/j.ejmech.2018.12.032
M3 - Article
C2 - 30611982
AN - SCOPUS:85059342148
SN - 0223-5234
VL - 164
SP - 408
EP - 422
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -