Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018)

ABSTRACT

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs.

Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes.

Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.     

PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 – 2014)

Introduction: Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin signal transduction pathway and has emerged as novel therapeutic strategy for the treatment of type 2 diabetes. PTP1B inhibitors enhance the sensibility of insulin receptor (IR) and have favorable curing effect for insulin resistance-related diseases. A large number of PTP1B inhibitors, either synthetic or isolated as bioactive agents from natural products, have developed and investigated for their ability to stimulate insulin signaling.

Areas covered: This review includes an updated summary (2011 – 2014) of PTP1B inhibitors that have been published in patent applications, with an emphasis on their chemical structure, mode of action and therapeutic outcomes. The usefulness of PTP1B inhibitors as pharmaceutical agents for the treatment of type 2 diabetes is also discussed.

Expert opinion: PTP1B inhibitors show beneficial effects to enhance sensibility of IR by restricting the activity of enzyme and have favorable curing effects. However, structural homologies in the catalytic domain of PTP1B with other protein tyrosine phosphatases (PTPs) like leukocyte common antigen-related, CD45, SHP-2 and T-cell-PTP present a challenging task of achieving selectivity. Thus, for therapeutic application of PTP1B inhibitors, highly selective molecules exhibiting desired effects without side effects are expected to find clinical application.     

Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus,obesity and related states of insulin resistance

Resistance to the cellular action of insulin, a fundamental pathophysiological defect accompanying the worldwide epidemic of obesity, is closely associated with the development of type 2 diabetes mellitus and the set of cardiovascular risk factors that constitute the "metabolic" syndrome. The development of novel pharmaceutical agents that help ameliorate insulin resistance will be potentially important not only for the prevention and treatment of diabetes, but also in reducing its associated cardiovascular risk profile. Studies on the cellular role of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves as a key negative regulator of the tyrosine phosphorylation cascade integral to the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide have provided crucial "proof-of-concept" data to show that eradicating or reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of over-nutrition and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cellular studies suggesting that PTPIB may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors that may serve as a novel type of "insulin sensitizer" in the management of type 2 diabetes and the cardiovascular / metabolic syndrome.     

Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2 cells <Emphasis Type="Italic">via</Emphasis> inhibiting protein tyrosine phosphatase 1B

Insulin resistance and protein tyrosine phosphatase 1B (PTP1B) overexpression are strongly associated with type 2 diabetes mellitus (T2DM), which is characterized by defects in insulin signaling and glucose intolerance. In a previous study, we demonstrated oligonol inhibits PTP1B and α-glucosidase related to T2DM. In this study, we examined the molecular mechanisms underlying the anti-diabetic effects of oligonol in insulin-resistant HepG2 cells. Glucose uptake was assessed using a fluorescent glucose tracer, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and the signaling pathway was investigated by western blotting. Oligonol significantly increased insulin-provoked glucose uptake and decreased PTP1B expression, followed by modulation of ERK phosphorylation. In addition, oligonol activated insulin receptor substrate 1 by reducing phosphorylation at serine 307 and increasing that at tyrosine 895, and enhanced the phosphorylations of Akt and phosphatidylinositol 3-kinase. Interestingly, it also reduced the expression of two key enzymes of gluconeogenesis (glucose 6-phosphatase and phosphoenolpyruvate carboxykinase), attenuated oxidative stress by scavenging/inhibiting peroxynitrite, and reactive oxygen species (ROS) generation, and augmented the expression of nuclear factor kappa B. These findings suggest oligonol improved the insulin sensitivity of insulin-resistant HepG2 cells by attenuating the insulin signaling blockade and modulating glucose uptake and production. Furthermore, oligonol attenuated ROS-related inflammation and prevented oxidative damage in our in vitro model of type 2 diabetes. These result indicate oligonol has promising potential as a treatment for T2DM.     

Design and Synthesis of Imidazolidine‐2,4‐Dione Derivatives as Selective Inhibitors by Targeting Protein Tyrosine Phosphatase‐1B Over T‐Cell Protein Tyrosine Phosphatase

Owing to its special role as a negative regulator in both insulin and leptin signaling, protein tyrosine phosphatase‐1B (PTP1B) has drawn considerable attention as a target for treating type 2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a series of compounds were discovered to inhibit PTP1B based on imidazolidine‐2,4‐dione by means of ‘core hopping’. A selective PTP1B inhibitor ( comp#h ) was identified, and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes.     

PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity

Coordinated tyrosine phosphorylation is essential for signalling pathways regulated by insulin and leptin. Type 2 diabetes and obesity are characterised by resistance to hormones insulin and leptin, possibly due to attenuated or diminished signalling from the receptors. Pharmacological agents capable of inhibiting the negative regulator(s) of the signalling pathways are expected to potentiate the action of insulin and leptin and therefore be beneficial for the treatment of Type 2 diabetes and obesity. A large body of data from cellular, biochemical, mouse and human genetic and chemical inhibitor studies have identified protein tyrosine phosphatase 1B (PTP1B) as a major negative regulator of both insulin and leptin signalling. In addition, evidence suggests that insulin and leptin action can be enhanced by the inhibition of PTP1B. Consequently, PTP1B has emerged as an attractive novel target for the treatment of both Type 2 diabetes and obesity. The link between PTP1B and diabetes and obesity has led to an avalanche of research dedicated to finding inhibitors of this phosphatase. With the combined use of structure and medicinal chemistry, several groups have demonstrated that it is feasible to obtain small-molecule PTP1B inhibitors with the requisite potency and selectivity. The challenge for the future will be to transform potent and selective small molecule PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.     

PTP1B inhibitors as potential therapeutics in the treatment of Type 2 diabetes and obesity

Coordinated tyrosine phosphorylation is essential for signalling pathways regulated by insulin and leptin. Type 2 diabetes and obesity are characterised by resistance to hormones insulin and leptin, possibly due to attenuated or diminished signalling from the receptors. Pharmacological agents capable of inhibiting the negative regulator(s) of the signalling pathways are expected to potentiate the action of insulin and leptin and therefore be beneficial for the treatment of Type 2 diabetes and obesity. A large body of data from cellular, biochemical, mouse and human genetic and chemical inhibitor studies have identified protein tyrosine phosphatase 1B (PTP1B) as a major negative regulator of both insulin and leptin signalling. In addition, evidence suggests that insulin and leptin action can be enhanced by the inhibition of PTP1B. Consequently, PTP1B has emerged as an attractive novel target for the treatment of both Type 2 diabetes and obesity. The link between PTP1B and diabetes and obesity has led to an avalanche of research dedicated to finding inhibitors of this phosphatase. With the combined use of structure and medicinal chemistry, several groups have demonstrated that it is feasible to obtain small-molecule PTP1B inhibitors with the requisite potency and selectivity. The challenge for the future will be to transform potent and selective small molecule PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.     

Inhibitors of protein tyrosine phosphatase 1B (PTP1B)

Recent studies have demonstrated that protein tyrosine phosphatase 1B (PTP1B) is involved in the down regulation of insulin signaling. Selective inhibitors of PTP1B hold much promise for the treatment of type 2 diabetes mellitus and obesity. Consequently much effort, by both industry and academia, has been devoted towards the development of PTP1B specific inhibitors. This article gives an overview of reports that have appeared in the primary scientific literature on the development of PTP1B inhibitors, starting from the days of early development up to September of 2002.     

Recent advances in protein tyrosine phosphatase 1B inhibitors

Type 2 diabetes and obesity are characterised by insulin and leptin resistance. Studies suggest that these may be due to defects in the insulin and leptin signalling pathways. Over the last decade, a considerable body of evidence has been amassed indicating that protein tyrosine phosphatase 1B (PTP1B) is involved in the downregulation of insulin and leptin signalling. Consequently, compounds that inhibit PTP1B have potential as therapeutics for treating Type 2 diabetes and obesity. This review covers recent advances in PTP1B inhibitors with an emphasis on recent attempts to create potent, selective and cell-permeable small-molecule inhibitors.     

Recent advances in protein tyrosine phosphatase 1B inhibitors

Type 2 diabetes and obesity are characterised by insulin and leptin resistance. Studies suggest that these may be due to defects in the insulin and leptin signalling pathways. Over the last decade, a considerable body of evidence has been amassed indicating that protein tyrosine phosphatase 1B (PTP1B) is involved in the downregulation of insulin and leptin signalling. Consequently, compounds that inhibit PTP1B have potential as therapeutics for treating Type 2 diabetes and obesity. This review covers recent advances in PTP1B inhibitors with an emphasis on recent attempts to create potent, selective and cell-permeable small-molecule inhibitors.     

Investigation of potential bioisosteric replacements for the carboxyl groups of peptidomimetic inhibitors of protein tyrosine phosphatase 1B: identification of a tetrazole-containing inhibitor with cellular activity

Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that, together with protein tyrosine kinases, control the level of intracellular tyrosine phosphorylation, thus regulating many cellular functions. PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. We previously reported a series of small molecular weight peptidomimetics as competitive inhibitors of PTP1B, with the most active analogues having K(i) values in the low nanomolar range. Furthermore, we confirmed that the O-carboxymethyl salicylic acid moiety is a remarkably effective novel phosphotyrosine mimetic. Because of the low cell permeability of this compound class, it was important to investigate the possibility of replacing one or both of the remaining carboxyl groups while maintaining PTP1B inhibitory activity. The analogues described herein further support the importance of an acidic functionality at both positions of the tyrosine head moiety. An important discovery was the ortho tetrazole analogue 29 (K(i) = 2.0 microM), which was equipotent to the dicarboxylic acid analogue 2 (K(i) = 2.0 microM). Solution of the X-ray cocrystal structure of the ortho tetrazole analogue 29 bound to PTP1B revealed that the tetrazole moiety is well-accommodated in the active site and binds in a fashion similar to the ortho carboxylate analogue 2 reported previously. This novel monocarboxylic acid analogue revealed significantly higher Caco-2 cell permeability as compared to all previous compounds. Furthermore, compound 29 exhibited modest enhancement of insulin-stimulated 2-deoxyglucose uptake by L6 myocytes.     

α-Methyl artoflavanocoumarin from <Emphasis Type="Italic">Juniperus chinensis</Emphasis> exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells

Diabetes mellitus is one of the greatest global health issues and much research effort continues to be directed toward identifying novel therapeutic agents. Insulin resistance is a challenging integrally related topic and molecules capable of overcoming it are of considerable therapeutic interest in the context of type 2 diabetes mellitus (T2DM). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling transduction and is regarded a novel therapeutic target in T2DM. Here, we investigated the inhibitory effect of α-methyl artoflavanocoumarin (MAFC), a natural flavanocoumarin isolated from Juniperus chinensis, on PTP1B in insulin-resistant HepG2 cells. MAFC was found to potently inhibit PTP1B with an IC₅₀ of 25.27 ± 0.14 µM, and a kinetics study revealed MAFC is a mixed type PTP1B inhibitor with a K _i value of 13.84 µM. Molecular docking simulations demonstrated MAFC can bind to catalytic and allosteric sites of PTP1B. Furthermore, MAFC significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells, down-regulated the phosphorylation of insulin receptor substrate (IRS)-1 (Ser307), and dose-dependently enhanced the protein levels of IRS-1, phosphorylated phosphoinositide 3-kinase (PI3K), Akt, and ERK1. These results suggest that MAFC from J. chinensis has therapeutic potential in T2DM by inhibiting PTP1B and activating insulin signaling pathways.     

Protein-tyrosine phosphatase 1B as a potential drug target for obesity

Obesity is increasing at an alarming rate and is considered by the World Health Organization as one of the top 10 epidemics worldwide. Resistance to leptin and insulin are likely to play a central role in obesity; thus, blocking inhibitors of these signaling pathways could prove useful in treating this disorder. Several lines of evidence have converged on protein tyrosine-phosphatase 1B (PTP1B) as one of the most important negative regulators of leptin as well as insulin signaling. Therefore, PTP1B appears to be a promising therapeutic candidate for the treatment of obesity. In this review, we discuss the role of PTP1B in leptin and insulin signaling, as well as its potential as a drug target in the treatment of obesity.     

New azolidinediones as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties

Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC(50) values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC(50) values in the range of 0.12-0.3 microM. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.     

Targeting protein tyrosine phosphatase to enhance insulin action for the potential treatment of diabetes

The increasing prevalence of type 2 diabetes has sparked interest in the development of agents that treat and prevent the disease. Mounting evidence indicates that protein tyrosine phosphatase (PTP)1B negatively regulates insulin and leptin signaling making it a prime target for enhancing insulin sensitivity and controlling body mass. Despite intense efforts, development of orally bioavailable small-molecule PTP1B inhibitors has been a challenge. This review focuses on recent advances in the validation of PTP1B and in the development of approaches to modulate its activity.     

蛋白酪氨酸磷酸酯酶-1B抑制剂的研究进展

蛋白酪酸磷酸酯酶-1B（PTP-1B）是蛋白酪氨酸磷酸脂酶（PTP）家族中最具代表性的成员，因其参与多种生理过程尤其是与机体对胰岛素的敏感性紧密相关，目前已经成为糖尿病和肥胖症治疗的新靶点。现从PTP简介、PTP-1B的结构、生理功能及6类抑制剂的结构性质等方面进行综述。     

Recent advances in the development of small molecule inhibitors of PTP1B for the treatment of insulin resistance and type 2 diabetes

Protein tyrosine phosphatases (PTPs) are a large family of diverse molecules that play an important role in both activating and attenuating a wide variety of cellular responses. One of these phosphatases, protein tyrosine phosphatase 1B (PTP1B), is clearly involved in attenuating insulin signaling, and much effort has been devoted towards the development of inhibitors of this enzyme as a therapeutic approach to treat insulin resistance and type 2 diabetes. This review will focus on recent advances in the development of small molecule inhibitors for PTP1B and the challenges for generating selective molecules. This review is largely limited to papers published within the last two years, since a review on this subject was published recently in this journal.     

Fucosterol activates the insulin signaling pathway in insulin resistant HepG2 cells via inhibiting PTP1B

Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. This study investigated the modulatory effects of fucosterol on the insulin signaling pathway in insulin-resistant HepG2 cells by inhibiting protein tyrosine phosphatase 1B (PTP1B). In addition, molecular docking simulation studies were performed to predict binding energies, the specific binding site of fucosterol to PTP1B, and to identify interacting residues using Autodock 4.2 software. Glucose uptake was determined using a fluorescent d-glucose analogue and the glucose tracer 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose, and the signaling pathway was detected by Western blot analysis. We found that fucosterol enhanced insulin-provoked glucose uptake and conjointly decreased PTP1B expression level in insulin-resistant HepG2 cells. Moreover, fucosterol significantly reduced insulin-stimulated serine (Ser307) phosphorylation of insulin receptor substrate 1 (IRS1) and increased phosphorylation of Akt, phosphatidylinositol-3-kinase, and extracellular signal- regulated kinase 1 at concentrations of 12.5, 25, and 50 µM in insulin-resistant HepG2 cells. Fucosterol inhibited caspase-3 activation and nuclear factor kappa B in insulin-resistant hepatocytes. These results suggest that fucosterol stimulates glucose uptake and improves insulin resistance by downregulating expression of PTP1B and activating the insulin signaling pathway. Thus, fucosterol has potential for development as an anti-diabetic agent.     

The Discovery of a Novel and Selective Inhibitor of PTP1B Over TCPTP: 3D QSAR Pharmacophore Modeling,Virtual Screening,Synthesis, and Biological Evaluation

Given the special role of insulin and leptin signaling in various biological responses, protein‐tyrosine phosphatase‐1B (PTP1B) was regarded as a novel therapeutic target for treating type 2 diabetes and obesity. However, owing to the highly conserved (sequence identity of about 74%) in active pocket, targeting PTP1B for drug discovery is a great challenge. In this study, we employed the software package Discovery Studio to develop 3D QSAR pharmacophore models for PTP1B and TCPTP inhibitors. It was further validated by three methods (cost analysis, test set prediction, and Fisher's test) to show that the models can be used to predict the biological activities of compounds without costly and time‐consuming synthesis. The criteria for virtual screening were also validated by testing the selective PTP1B inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective inhibitor of PTP1B over TCPTP. After that, a most likely binding mode was proposed. Thus, the findings reported here may provide a new strategy in discovering selective PTP1B inhibitors.     

Protein tyrosine phosphatase 1B inhibition: opportunities and challenges

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as one of the key negative regulators of insulin and leptin signal transduction pathways. PTP1B deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than the wild-type control mice. Inhibiting PTP1B action using antisense oligonucleotides and small molecule inhibitors represents novel therapeutic approach for the treatment of insulin resistance, type II diabetes, and obesity. The rapid development of this field is evidenced by the increasing number of patents and publications in recent years. This review will highlight the recent advances in various approaches for attenuating PTP1B action, particularly small molecule PTP1B inhibitors, and the challenges associated with developing PTP1B inhibitors with drug like properties.