Potent Protein Tyrosine Phosphatase 1B Inhibitors Research Articles

Toward the identification of a reliable 3D-QSAR model for the protein tyrosine phosphatase 1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B) is an intracellular non-receptor phosphatase that is implicated in signal transduction of insulin and leptin pathways, thus PTP1B is considered as potential target for treating type II diabetes and obesity. The present article is an attempt to formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of compounds possessing PTP1B inhibitory activities using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The optimum template ligand-based models are statistically significant with great CoMFA (R2cv = 0.600, R2pred = 0.6760) and CoMSIA (R2cv = 0.624, R2pred = 0.8068) values. Molecular docking was employed to elucidate the inhibitory mechanisms of this series of compounds against PTP1B. In addition, the CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of PTP1B active site. The knowledge of structure-activity relationship and ligand-receptor interactions from 3D-QSAR model and molecular docking will be useful for better understanding the mechanism of ligand-receptor interaction and facilitating development of novel compounds as potent PTP1B inhibitors.

Molecular docking and DFT based QSAR study on Oleanolic acid derivatives as Protein-tyrosine phosphatase 1B inhibitors

Protein-tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of type 2 diabetes. Oleanolic acid and its derivatives were found to be potent PTP1B inhibitors. In this study, we have performed QSAR studies followed by molecular docking. The docking study shows that most of the ligands can form hydrogen bonds with ARG24 and/or ARG254. Two quantitative structure activity relationships models have been constructed using different descriptors and the significance of these models is judged on the basis of correlation, Fischer F test, and quality factor (Q). It is believed that this study is helpful in the design of potent PTP1B inhibitors.

Exploring sulfonate esters of 5-arylidene thiazolidine-2,4-diones as PTP1B inhibitors with anti-hyperglycemic activity

Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signaling pathway, hence considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. A series of eleven aryl/alkyl sulfonyloxy-5-arylidene thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for PTP1B inhibitory activity and in vivo for anti-hyperglycemic activity. The introduction of aryl/alkyl sulfonate ester moiety was anticipated to yield PTP1B inhibitors with significant potency. Docking results revealed their bidentate nature of binding, and further helped in understanding the binding mode of ligands inside PTP1B enzyme. Compounds 13 and 14 were found to be potent PTP1B inhibitors with IC50 8.53 and 6.89 µM, respectively. Compounds 13, 14, and 18 have also shown significant lowering of blood glucose level as compared to pioglitazone.

Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity.

This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure-activity relationships. Intranasal administration of PTP1B inhibitors at ≥0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action.

Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor

BackgroundProtein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results.ResultsStudies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5.ConclusionWe report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

Potential of Polygonum cuspidatum Root as an Antidiabetic Food: Dual High-Resolution α-Glucosidase and PTP1B Inhibition Profiling Combined with HPLC-HRMS and NMR for Identification of Antidiabetic Constituents.

The worldwide increasing incidence of type 2 diabetes has fueled an intensified search for food and herbal remedies with preventive and/or therapeutic properties. Polygonum cuspidatum Siebold & Zucc. (Polygonaceae) is used as a functional food in Japan and South Korea, and it is also a well-known traditional antidiabetic herb used in China. In this study, dual high-resolution α-glucosidase and protein-tyrosine phosphatase 1B (PTP1B) inhibition profiling was used for the identification of individual antidiabetic constituents directly from the crude ethyl acetate extract and fractions of P.cuspidatum. Subsequent preparative-scale HPLC was used to isolate a series of α-glucosidase inhibitors, which after HPLC-HRMS and NMR analysis were identified as procyanidin B2 3,3″-O-digallate (3) and (-)-epicatechin gallate (5) with IC50 values of 0.42 ± 0.02 and 0.48 ± 0.0004 μM, respectively, as well as a series of stilbene analogues with IC50 value in the range from 6.05 ± 0.05 to 116.10 ± 2.04 μM. In addition, (trans)-emodin-physcion bianthrone (15b) and (cis)-emodin-physcion bianthrone (15c) were identified as potent PTP1B inhibitors with IC50 values of 2.77 ± 1.23 and 7.29 ± 2.32 μM, respectively. These findings show that P.cuspidatum is a potential functional food for management of type 2 diabetes.

Synthesis, biological evaluation and in silico studies of 5-(3-methoxybenzylidene)thiazolidine-2,4-dione analogues as PTP1B inhibitors

PTP1B (protein tyrosine phosphatase 1B) dephosphorylates the insulin receptor substrate and thus acts as a negative regulator of the insulin and leptin signalling pathway. Recently, it has been considered as a new therapeutic target of intervention for the treatment of type2 diabetes. A series of aryl/alkylsulfonyloxy-5-(3-methoxybenzylidene)thiazolidine-2,4-dione derivatives were synthesized, screened in vitro for their PTP1B inhibitory activity and in vivo for anti-hyperglycaemic activity. Docking results further helped in understanding the nature of interactions governing the binding mode of ligands inside the active site of PTP1B. Among the synthesized compounds, 13 and 16 were found to be potent PTP1B inhibitors having IC50 of 7.31 and 8.73μM respectively. Significant lowering of blood glucose level was observed in some of the synthesized compounds in in vivo study.

Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach.

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors.

Multiple machine learning based descriptive and predictive workflow for the identification of potential PTP1B inhibitors

In insulin and leptin signaling pathway, Protein-Tyrosine Phosphatase 1B (PTP1B) plays a crucial controlling role as a negative regulator, which makes it an attractive therapeutic target for both Type-2 Diabetes (T2D) and obesity. In this work, we have generated classification models by using the inhibition data set of known PTP1B inhibitors to identify new inhibitors of PTP1B utilizing multiple machine learning techniques like naïve Bayesian, random forest, support vector machine and k-nearest neighbors, along with structural fingerprints and selected molecular descriptors. Several models from each algorithm have been constructed and optimized, with the different combination of molecular descriptors and structural fingerprints. For the training and test sets, most of the predictive models showed more than 90% of overall prediction accuracies. The best model was obtained with support vector machine approach and has Matthews Correlation Coefficient of 0.82 for the external test set, which was further employed for the virtual screening of Maybridge small compound database. Five compounds were subsequently selected for experimental assay. Out of these two compounds were found to inhibit PTP1B with significant inhibitory activity in in-vitro inhibition assay. The structural fragments which are important for PTP1B inhibition were identified by naïve Bayesian method and can be further exploited to design new molecules around the identified scaffolds. The descriptive and predictive modeling strategy applied in this study is capable of identifying PTP1B inhibitors from the large compound libraries.

Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents

New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signaling.

Protein tyrosine phosphatase 1B and α-glucosidase inhibitory activities of Pueraria lobata root and its constituents

Ethnopharmacological relevancePueraria lobata root was used to treat wasting-thirst regarded as diabetes mellitus and was included in the composition of Okcheonsan, which is prescribed for thirst-waste in traditional Chinese medicine. Aim of the studyThe objective of this study was to evaluate the anti-diabetic potential of the root of Pueraria lobata and its constituents via protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitory activities. Materials and methodsIn this study, anti-diabetic activities of the 70% ethanolic (EtOH) extract from P. lobata roots and its solvent soluble fractions with the isolated compounds were investigated by evaluating in vitro PTP1B and α-glucosidase inhibitory activities. We also examined the potentials of active compounds as PTP1B and α-glucosidase inhibitors via enzyme kinetics and in silico molecular docking simulation between the enzymes and active compounds. ResultsTriterpenoids lupeol and lupenone were potent PTP1B inhibitors with IC50 values of 38.89±0.17 and 15.11±1.23μM. Kinetic study using the Lineweaver-Burk and Dixon plots demonstrated that these compounds showed a noncompetitive-type inhibition against PTP1B with respective Ki values of 13.88μM and 21.24μM. In addition, molecular docking simulation showed lupeol and lupenone has negative binding energy values of −8.03 and −8.56kcal/mol. Considering the α-glucosidase inhibitory potential, daidzein, genistein, and calycosin exhibited the most potent α-glucosidase inhibition with IC50 values of 8.58±0.94, 2.37±0.52 and 6.84±1.58μM, respectively. Kinetic study demonstrated that these 3 compounds showed a noncompetitive-type inhibition against α-glucosidase with respective Ki values of 17.64μM, 5.03μM and 13.83μM. Moreover, molecular docking simulation showed daidzein, genistein and calycosin has more lower binding energy (−7.16kcal/mol, −7.42kcal/mol and −7.31kcal/mol) with higher binding affinity and tight binding capacity in the molecular docking studies than standard ligand α-D-glucose (−6.74kcal/mol). ConclusionOur results of the present study clearly demonstrate the potential of P. lobata extract and its constituents to inhibit PTP1B and α-glucosidase, contributing to the development of therapeutic or preventive agents that can be used in the treatment of diabetes.

Rational design, synthesis, and structure–activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure–activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Identification of PTP1B and α-Glucosidase Inhibitory Serrulatanes from Eremophila spp. by Combined use of Dual High-Resolution PTP1B and α-Glucosidase Inhibition Profiling and HPLC-HRMS-SPE-NMR.

According to the International Diabetes Federation, type 2 diabetes (T2D) has reached epidemic proportions, affecting more than 382 million people worldwide. Inhibition of protein tyrosine phosphatase-1B (PTP1B) and α-glucosidase is a recognized therapeutic approach for management of T2D and its associated complications. The lack of clinical drugs targeting PTP1B and side effects of the existing α-glucosidase drugs, emphasize the need for new drug leads for these T2D targets. In the present work, dual high-resolution PTP1B and α-glucosidase inhibition profiles of Eremophila gibbosa, E. glabra, and E. aff. drummondii "Kalgoorlie" were used for pinpointing α-glucosidase and/or PTP1B inhibitory constituents directly from the crude extracts. A subsequent targeted high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy (HPLC-HRMS-SPE-NMR) analysis and preparative-scale HPLC isolation led to identification of 21 metabolites from the three species, of which 16 were serrulatane-type diterpenoids (12 new) associated with either α-glucosidase and/or PTP1B inhibition. This is the first report of serrulatane-type diterpenoids as potential α-glucosidase and/or PTP1B inhibitors.

High-resolution PTP1B inhibition profiling combined with high-performance liquid chromatography–high-resolution mass spectrometry–solid-phase extraction–nuclear magnetic resonance spectroscopy: Proof-of-concept and antidiabetic constituents in crude extract of Eremophila lucida

Type 2 diabetes (T2D) constituted 90% of the global 387 million diabetes cases in 2014. The enzyme protein-tyrosine phosphatase 1B (PTP1B) has been recognized as a therapeutic target for treatment of T2D and its adverse complications. With the aim of accelerating the investigation of complex natural sources, such as crude plant extracts, for potential PTP1B inhibitors, we have developed a bio-analytical platform combining high-resolution PTP1B inhibition profiling and high-performance liquid chromatography–high-resolution mass spectrometry–solid-phase extraction–nuclear magnetic resonance spectroscopy, i.e., HR-bioassay/HPLC–HRMS–SPE–NMR. Human recombinant PTP1B enzyme was used for the microplate-based PTP1B inhibition assay, which was optimized for pH and substrate concentration to be compatible with rate measurements within the 10min incubation time. Subsequently, analytical-scale HPLC-based microfractionation followed by colorimetric microplate-based PTP1B bioassaying enabled construction of a high-resolution inhibition profile corresponding to the HPLC profile. The high-resolution PTP1B inhibition profiling was validated using an artificial mixture of known PTP1B inhibitors and non-inhibiting compounds as negative controls. Finally, a proof-of-concept study with a real sample was performed using crude ethyl acetate extract of the phytochemically hitherto unexplored plant Eremophila lucida. This led to the identification of the first viscidane type diterpene, i.e., 5-hydroxyviscida-3,14-dien-20-oic acid (9) as PTP1B inhibitor with an IC50 value of 42.0±5.9μM. In addition, a series of flavonoids, i.e., luteolin (1), dinatin (3a), tricin (3b), 3,6-dimethoxyapigenin (4), jaceidin (5), and cirsimaritin (6) as well as a cembrene diterpene, (3Z, 7E, 11Z)-15-hydroxycembra-3,7,11-trien-19-oic acid (8), were also identified for the first time from E. lucida.

Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic

Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.

ChemInform Abstract: Natural and Semisynthetic Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors as anti‐Diabetic Agents

AbstractReview: 94 refs.

Small Molecules as Potent Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors Documented in Patents from 2009 to 2013

Diabetes mellitus, including type 1 and type 2 diabetes mellitus (2-DM) are the main threats to human health in the worldwide. Protein tyrosine phosphatase 1B (PTP1B) is a promising molecular level legitimate therapeutic target in the effective management of 2-DM. For the search of potent PTP1B inhibitors, much investigation has revealed a large number of small-molecule compounds obtained from natural sources or prepared by synthesis/semi-synthesis with various skeletons and promising anti-PTP1B activities in the treatment of 2-DM. Although some reviews on the development of PTP1B inhibitors have been published, they were mainly concentrated on the results reported in journal articles. In this review, we will provide an overview of the developments of the potent PTP1B inhibitors claimed in recent patents during the past five years (2009-2013) with their structural features and biological features, as well as the structure-activity relationships (SARs) and strategies for finding potent and specific PTP1B inhibitors. This paper will provide valuable information for understanding the current anti-PTP1B investigation and developing potent PTP1B inhibitors as treating 2-DM drugs.

Natural and semisynthetic protein tyrosine phosphatase 1B (PTP1B) inhibitors as anti-diabetic agents

Natural products offered more opportunities to develop new drugs and leading compounds as potent PTP1B inhibitors for treating T2DM.

Caffeoylquinic acid derivatives isolated from the aerial parts of Gynura divaricata and their yeast α-glucosidase and PTP1B inhibitory activity

The phytochemical investigation of natural products of Gynura divaricata led to the isolation of eleven caffeoylquinic acid derivatives. They were characterized by spectrometric methods as 5-O-caffeoylquinic acid (1), 5-O-p-coumaroylquinic acid (2), 5-O-feruloylquinic acid (3), methyl 5-O-caffeoylquinate (4), 3,4-dicaffeoylquinic acid (5), 3,5-dicaffeoylquinic acid (6), 4,5-dicaffeoylquinic acid (7), methyl 3,4-dicaffeoylquinate (8), methyl 3,5-dicaffeoylquinate (9), methyl 4,5-dicaffeoylquinate (10) and ethyl 4,5-dicaffeoylquinate (11). The individual compounds were screened for the inhibition of yeast α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) using in vitro assays. Among the isolated compounds, 3,4-dicaffeoylquinic acid (5), 4,5-dicaffeoylquinic acid (7), methyl 3,4-dicaffeoylquinate (8) and methyl 4,5-dicaffeoylquinate (10) exhibited significant inhibitory activities against α-glucosidase. In addition, 5-O-p-coumaroylquinic acid (2), 3,5-dicaffeoylquinic acid (6) and 4,5-dicaffeoylquinic acid (7) had considerable inhibitory effect against PTP1B. Based on these findings, the caffeoylquinic acid derivatives were deduced to be potentially responsible for the anti-diabetic activity of G. divaricata. The preliminary structure–activity relationship study suggests that the number and positioning of caffeoyl groups in the quinic acid derivatives are important for both α-glucosidase and PTP1B inhibitory potency. Moreover, the corresponding methyl esters of some dicaffeoylquinic acids have enhanced inhibitory activity against yeast α-glucosidase.

Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B. The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests. Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity. Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.