Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy

Tang, Yan; Zhang, Xiaolin; Chen, Zheng; Yin, Wenwen; Nan, Guanglei; Tian, Jinying; Ye, Fei; Xiao, Zhiyan

doi:10.1016/j.apsb.2018.05.001

Cited by 15 publications

(9 citation statements)

References 21 publications

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“…A decoy set including 1554 compounds was employed to validate the CBP and PLIF models by assessing their ability to discriminate the active from the inactive. The decoy set consisted of 1500 presumably inactive compounds from the ACD-3D database and 54 known PTP1B allosteric inhibitors, ,,, among which 28 are active compounds and 26 are inactive ones. As represented by the red lines in Figure A,B, the CBP model recognized 20 of the 28 active compounds when only 23 compounds were screened, and the PLIF model could identify 26 of the 28 active ones within the top 28 screened.…”

Section: Resultsmentioning

confidence: 99%

“…Validation of the Pharmacophore Models. To evaluate the capability of CBP and PLIF models to distinguish active compounds from inactive ones, a decoy set consisting of 28 active compounds and 26 inactive compounds taken from published PTP1B allosteric inhibitors 10,11,13,16 as well as 1500 presumably inactive compounds from the ACD-3D database was generated. The chemical structures and properties of the 1554 compounds in the decoy set are accessible as Supporting Data.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Among them, compound 2 (Figure ) was identified as a potent PTP1B inhibitor with excellent selectivity over other PTPs and significant in vivo insulin-sensitizing effects. Therefore, targeting the alternative allosteric site of PTP1B could be a promising approach to address the issues of selectivity and oral availability. − Furthermore, the druggability assessment of both allosteric and catalytic sites of PTP1B also suggested that the allosteric site could be a more viable site for the development of druglike PTP1B inhibitors …”

Section: Introductionmentioning

confidence: 99%

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Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site

Yang

Zhang

Tian

et al. 2021

J. Chem. Inf. Model.

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Protein tyrosine phosphatase 1B (PTP1B) is an intractable target for drug discovery due to its conservative and cationic catalytic site. Targeting alternative allosteric sites of PTP1B is a promising strategy to achieve specificity and bioavailability. A hierarchical virtual screening based on a previously identified allosteric site was applied to search for potential PTP1B inhibitors with better pharmacological profiles. Four potent PTP1B inhibitors (H1, H3, H7, and H9) with structures distinct from known inhibitors were identified. Among them, H3 and H9 demonstrated evident selectivity to PTP1B over homologous T-cell protein tyrosine phosphatase (TCPTP) and SHP2. Molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) calculations recognized Phe280, Phe196, Leu192, and Asn193 as key residues responsible for potent allosteric inhibition and excellent PTP selectivity. The results not only expand the structural diversity but also aid the future molecular design of PTP1B allosteric inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site

Yang

Zhang

Tian

et al. 2021

J. Chem. Inf. Model.

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“…Obesity, type 2 diabetes and non-alcohol fatty liver disease are aspects of metabolic syndrome, which is a major public health problem worldwide36., 37., 38., 39., 40.. Thermogenesis is considered a therapeutic target for obesity 41 .…”

Section: Discussionmentioning

confidence: 99%

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Sun

Pang

Wang

et al. 2019

Acta Pharmaceutica Sinica B

134

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Since metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro- β -muricholic acid (T β MCA). The intestinal FXR signaling was suppressed but remained unchanged in the liver. This study is of potential translational significance in determining the role of gut microbiota-mediated bile acid metabolism in modulating diet-induced glucose intolerance and hepatic steatosis in the hamster.

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“…The drug targets for insulin sensitizers include PPARγ [ 9 ] and PTP1B [ 10 ]. PPARγ agonists are not on the recommendation list, while PTP1B inhibitors need regulatory approval for clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Uncarboxylated osteocalcin ameliorates hepatic glucose and lipid metabolism in KKAy mice via activating insulin signaling pathway

Zhang

Wang

et al. 2019

Acta Pharmacol Sin

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Osteocalcin, expressed in osteoblasts of the bone marrow, undergoes post-translational carboxylation and deposits in mineralized bone matrix. A portion of osteocalcin remains uncarboxylated (uncarboxylated osteocalcin, GluOC) that is released into blood where it functions as a hormone to regulate insulin secretion and insulin sensitivity. As insulin resistance is closely associated with metabolic syndrome, this study is aimed to elucidate how GluOC regulates glucose and lipid metabolism in KKAy mice, an animal model displaying obese, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. GluOC (3, 30 ng/g per day, ig) was orally administered to female KKAy mice for 4 weeks. Whole-body insulin sensitivity, glucose metabolism, hepatic steatosis, dyslipidemia were examined using routine laboratory assays. We found that GluOC administration significantly enhanced insulin sensitivity in KKAy mice by activating hepatic IRβ/PI3K/Akt pathway and elevated the whole-body insulin sensitivity with decreased FPI and HOMA-IR index. Furthermore, GluOC administration alleviated hyperglycemia through suppressing gluconeogenesis and promoting glycogen synthesis in KKAy mice and in cultured hepatocytes in vitro. Moreover, GluOC administration dose-dependently ameliorated dyslipidemia and attenuated hepatic steatosis in KKAy mice by inhibiting hepatic de novo lipogenesis and promoting fatty-acid β-oxidation. These results demonstrate that GluOC effectively enhances hepatic insulin sensitivity, improves hyperglycemia and ameliorates hepatic steatosis in KKAy mice, suggesting that GluOC could be a promising drug candidate for treating metabolic syndrome.

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Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy

Cited by 15 publications

References 21 publications

Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site

Integrated Approach to Identify Selective PTP1B Inhibitors Targeting the Allosteric Site

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Uncarboxylated osteocalcin ameliorates hepatic glucose and lipid metabolism in KKAy mice via activating insulin signaling pathway

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