Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

Fangzhou Xie; Yaoyao Liang; Yu Xia; Shuhua Luo; Faqin Jiang; Lei Fu

doi:10.1016/j.bioorg.2019.103273

Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

Fangzhou Xie, Yaoyao Liang, Yu Xia, Shuhua Luo, Faqin Jiang, Lei Fu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC₅₀ = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (P_app = 2.41 × 10⁻⁶ cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.

Original language	English
Article number	103273
Journal	Bioorganic Chemistry
Volume	92
DOIs	https://doi.org/10.1016/j.bioorg.2019.103273
Publication status	Published - Nov 2019
Externally published	Yes

Keywords

2-Ethoxy-4-(methoxymethyl)benzamide
PTP1B Inhibitors
Selectivity
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bioorg.2019.103273

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title = "Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors",

abstract = "Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC50 = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (Papp = 2.41 × 10−6 cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.",

keywords = "2-Ethoxy-4-(methoxymethyl)benzamide, PTP1B Inhibitors, Selectivity, Type 2 diabetes",

author = "Fangzhou Xie and Yaoyao Liang and Yu Xia and Shuhua Luo and Faqin Jiang and Lei Fu",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

doi = "10.1016/j.bioorg.2019.103273",

language = "English",

volume = "92",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

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TY - JOUR

T1 - Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

AU - Xie, Fangzhou

AU - Liang, Yaoyao

AU - Xia, Yu

AU - Luo, Shuhua

AU - Jiang, Faqin

AU - Fu, Lei

PY - 2019/11

Y1 - 2019/11

N2 - Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC50 = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (Papp = 2.41 × 10−6 cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.

AB - Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC50 = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (Papp = 2.41 × 10−6 cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.

KW - 2-Ethoxy-4-(methoxymethyl)benzamide

KW - PTP1B Inhibitors

KW - Selectivity

KW - Type 2 diabetes

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U2 - 10.1016/j.bioorg.2019.103273

DO - 10.1016/j.bioorg.2019.103273

M3 - Article

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AN - SCOPUS:85072168500

SN - 0045-2068

VL - 92

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 103273

ER -

Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

Abstract

Keywords

UN SDGs

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