苯氧乙酸类PTP1B抑制剂的设计、合成及活性研究

蛋白酪氨酸磷酸酶(protein tyrosine phosphatase, PTP) 1B是治疗2型糖尿病的潜在靶点。已知的PTP1B抑制剂多数为磷酸酪氨酸(pTyr)模拟物。本文以苯氧乙酸片段模拟pTyr,设计合成了苯氧乙酸类化合物2a～2g和3a～3c。其中,化合物2a～2g对PTP1B具有显著的抑制活性,化合物2g对PTP1B的IC50值达到0.42μmol·L^-1。化合物2f可提高胰岛素抵抗(IR)小鼠的胰岛素敏感性,并降低其血总胆固醇水平,与胰岛素增敏剂罗格列酮的作用类似。上述研究结果提示PTP1B抑制剂可能对2型糖尿病及其并发症具有综合治疗作用。     

蛋白质酪氨酸磷酸酯酶1B(PTP1B)抑制剂研究进展

蛋白质酪氨酸磷酸酯酶1B(PTP1B)在胰岛素信号传导过程中起负调节作用,是治疗糖尿病和肥胖症的潜在靶点.本文按作用位点对近年来研究的PTP1B抑制剂进行综述,分析了N-草酰胺苯甲酸类化合物、水杨酸类化合物、取代苯乙酮及肉桂酸类化合物、氨基磺酸类化合物、拟肽类物质、噻吩及苯并噻吩类化合物、苯并呋喃磺酰胺类化合物和哒嗪类化合物八大类抑制剂的结构及药理活性.     

PTP1B作为药物靶点的研究进展

Protein tyrosine phosphatase 1B(PTP1B)是治疗2型糖尿病以及肥胖的潜在的,有效的靶点.最近,其作为抗肿瘤的靶点得到了很多关注.这篇文章简要介绍了PTP1B在不同疾病相关信号通路中的作用以及人们在发现PTP1B抑制剂上已经取得的成果.目前,以PTP1B为靶点的小分子药物发现仍面临很多困难,经过努力,希望在不久的将来会找到更有潜力并且更加有效的PTP1B临床抑制剂药物.     

PTP1B抑制活性真菌F956的鉴定和代谢产物研究

目的 研究PTP1B抑制活性真菌菌株F956及其代谢产物。方法 通过形态观察及ITS序列系统发育分析鉴定活性菌株F956;对其发酵产物进行分离纯化获得单体化合物并通过综合波谱解析确定代谢产物的化学结构。对得到的化合物进行分子对接及PTP1B抑制活性评价。结果 F956鉴定为Mucor fragilis(易脆毛霉);从其代谢产物中得到2个具有PTP1B抑制活性的化合物F956-5和F956-6,其中F956-5与化合物JBIR-12相同,F956-6为JBIR-12的13位羟基甲基化衍生物,分子对接结果显示F956-6可占据PTP1B的活性位点;其对PTP1B的IC50分别为7.12和13.92μg/mL。 结论 化合物F956-5(JBIR-12)和F956-6由易脆毛霉产生及其对PTP1B的抑制活性均为首次报道。     

基于Hypogen药效团模型发现潜在的PTP1B抑制剂

目的 采用计算机辅助药物设计的方法发现潜在的PTP1B抑制剂。方法 应用3D-QSAR药效团模型中的Hypogen模块构建药效团模型,成本分析、测试集预测和Fisher检验3种方法来验证该模型可用于预测化合物的生物活性的能力。运用该药效团模型对ZINC数据库进行虚拟筛选,得到Fit value值较高的先导化合物ZINC35671983。根据药效团的特征对ZINC35671983进行结构改造得到相应化合物。将化合物用ADMET进行成药预测。结果 ZINC35671983进行结构改造筛选获得92个化合物,筛出对接得分高于ZINC3567198的8个化合物。结论 发现8个潜在的PTP1B抑制剂,这有助于发现新的PTP1B先导化合物。     

芒果苷衍生物的合成及其PTP1B酶抑制活性研究

目的设计合成一系列芒果苷衍生物并进行体外蛋白酪氨酸磷酸酶1B（PTP1B）抑制活性实验。方法利用亲核取代反应在芒果苷上引入疏水苄基,设计合成8个新化合物4~11,采用比色法对化合物进行PTP1B抑制活性研究。结果设计合成的8个化合物对PTP1B酶都有一定的抑制作用。结论芒果苷衍生物的活性明显好于芒果苷本身的活性,苄基的对位取代活性要优于邻位和间位取代,且苄基上氯原子取代的衍生物要高于其它原子取代的化合物活性。     

蛋白酪氨酸磷酸酶1B及其小分子抑制剂的研究进展

蛋白酪氨酸磷酸酶1B（PTP-1B）是胰岛素和瘦素信号传导通路的负调节因子。目前,作为糖尿病和肥胖症治疗的新靶点,PTP-1B抑制剂的研究引起了广泛的关注。现从PTP-1B简介、生理功能以及抑制剂的结构性质等方面进行综述。     

PTP1B抑制剂改善胰岛素抵抗作用的实验研究

目的：研究苯并呋喃．苯氧乙酸类化合物CCF06240对蛋白酪氨酸磷酸酶1B（Protein tyrosine phosphates 1B,PTP1B）活性的抑制作用,探讨其对高脂饮食诱导的胰岛素抵抗小鼠的胰岛素增敏作用及其作用机制。方法：以体外酶学方法观察药物对基因重组人PTP1B活性的影响。雄性C57BL／6j小鼠经高脂高糖饲料诱导形成肥胖的胰岛素抵抗动物模型（IRF）。以小鼠口服葡萄糖耐量实验（OGTT）中葡萄糖负荷后血糖水平的变化评价动物对葡萄糖的耐受能力。采用胰岛素耐量实验（ITT）和正常葡萄糖水平的高胰岛素钳夹（正糖钳）实验评价机体的胰岛素敏感性。结果：化合物CCF06240对基因重组人PTP1B活性有较强的抑制作用,其IC50为9．6×10^-7M。连续灌胃给予IRF小鼠CCF0624010mg／kg／day,与模型对照组比较,CCF06240组动物体重降低17％（p〈0．001）,血甘油二酯降低77％,总胆固醇降低7I％,非禁食状态下血糖降低20％,禁食2h后血糖降低25％（p〈0．001）。     

以PTP1B为靶点的胰岛素增敏剂的实验研究

蛋白酪氨酸磷酸酶1B（protein tyrosine phosphatase 1B，PTP1B）是蛋白酪氨酸磷酸酶家族中的主要成员之一，在胰岛素信号传导系统的平衡中，起着重要作用。胰岛素信号传导系统主要是通过信号分子的磷酸化程度来调节的。信号分子的酪氨酸磷酸化与去磷酸化的平衡，对胰岛素发挥生物效应极其重要。阿PTP1B是催化分子酪氨酸去磷酸化的蛋白酪氨酸磷酸酶家族中的主要成员之一，可以使胰岛素受体底物（IRSs）等许多信号分子的酪氨酸去磷酸化而失活，在胰岛素信号传导系统中起着重要作用。阿PTP1B抑制剂已成为胰岛素增敏剂的靶点之一。     

酪氨酸蛋白磷酸酯酶1B抑制剂的构效关系

介绍了最近几年来关于酪氨酸蛋白磷酸酯酶1B作用的机制以及通过各种途径发现的结构新颖的小分子抑制剂的构效关系研究进展。酪氨酸蛋白磷酸酯酶1B在胰岛素依赖的信号传导途径中发挥着非常重要的作用,并作为一个潜在的治疗2型糖尿病和肥胖的作用靶点日益受到广泛的关注。在其晶体结构被报道后,强效和选择性好的抑制剂更成为研制开发新药的焦点。     

PTP1B inhibitors from Ardisia japonica

In bioassay-directed isolation from the whole plant of Ardisia japonica, sixteen known compounds: chrysophanol (1), physcion (2), oleanolic acid (3), euscaphic acid (4), tormentic acid (5), quercetin (6), quercitrin (7), myricitrin (8), kaempferol 3-O-α-l-rhamnopyranoside (9), cyclamiretin A 3-O-α-l-rhamnopyranosyl(1→4)-β-d-glucopyranosyl(1→2)-[β-d-glucopyranosyl(1→4)]-α-l-arabinopyranoside (10), (7E)-9-hydroxymegastigma-4, 7-dien-3-on-9-O-β-d-glucopyranoside (11), bergenin (12), norbergenin (13), rutin (14), kaempferol 3,7-O-α-l-dirhamnopyranoside (15), (?)-epigallacatechin 3-O-gallate (16) were obtained. Compounds 1–5, 9, 11 and 14–16 have not been reported previously from this plant. Among these isolates, 2, 3, 6 and 12 showed moderate bioactivity against PTP1B in vitro with IC₅₀ values of 121.50, 23.90, 28.12 and 157?μM, respectively.     

合成类蛋白酪氨酸磷酸酶1B抑制剂专利现状分析

蛋白酪氨酸磷酸酶1B（PTP1B）是治疗2型糖尿病的潜在的重要靶点,与肥胖、肿瘤也具有密切关系,本文从专利分布和布局的角度出发,选择以PTP1B抑制剂作为主题,使用关键词对全球专利数据库中的全球发明专利申请进行了检索,得到相关的发明专利申请,对上述数据进行人工筛选分类,重点对合成类PTP1B抑制剂专利态势作了研究分析,以期能够为该领域药物的开发与仿制提供有益的借鉴与参考。     

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.     

Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and glucosidase inhibitory activity of compounds isolated from Agrimonia pilosa

Context: Despite phytochemical studies of Agrimonia pilosa Ledeb. (Rosaceae), the antidiabetic effects of this plant are unknown.

Objective: This study characterizes the isolated compounds from the aerial parts of A. pilosa and evaluates their PTP1B and α-glucosidase inhibitory properties.

Materials and methods: Ethanol extract of A. pilosa was found to inhibit 64% PTP1B activity at 30?μg/mL. The ethanol extract was partitioned with methylene chloride, ethyl acetate, n-butanol, and water fractions. Among these, the ethyl acetate fraction displayed the most potent PTP1B activity. The ethyl acetate extract was separated by chromatographic methods to obtain flavonoids and triterpenoids (1–11); which were evaluated for their inhibitory effects on PTP1B activity with p-nitrophenyl phosphate (p-NPP) as a substrate, and also α-glucosidase enzyme.

Results: Compounds 1–11 were identified as apigenin-7-O-β-d-glucuronide-6″-methyl ester, triliroside, quercetin-7-O-β-d-glycoside, quercetin-3-O-β-d-glycoside, kaempferol, kaempferol-3-O-α-l-rhamnoside, β-sitosterol, ursolic acid, tormentic acid, methyl 2-hydroxyl tricosanoate, and palmitic acid. Compounds 8, 9, and 11 displayed inhibitory effects on PTP1B activity with IC₅₀ values of 3.47?±?0.02, 0.50?±?0.06, and 0.10?±?0.03?μM, respectively. Compounds 3, 4, 6, and 9 exhibited inhibition of the α-glucosidase activity with IC₅₀ values of 11.2?±?0.2, 29.6?±?0.9, 28.5?±?0.1, and 23.8?±?0.4?μM, respectively.

Discussion and conclusion: As major ingredients of A. pilosa, compounds 1, 6, 8, and 9 showed the greatest inhibitory potency on PTP1B activity. Compounds 3, 6, 8, and 9 also showed potent inhibitory effects on α-glucosidase enzyme. This result suggested the potential of these compounds for developing antidiabetic agents.     

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.     

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity

This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl–N′-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action. Using prove of concept in vivo study, we show that dual-targeting compound 7a has a disease-modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.     

Synthesis,SAR and docking studies of substituted aryl phenylthiazolyl phenylcarboxamide as potential protein tyrosine phosphatase 1B (PTP1B) inhibitors

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II . Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B‐binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.     

A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics

Diabetes mellitus (DM) is a serious global health concern affecting over 500 million people. To put it simply, it is one of the most dangerous metabolic illnesses. Insulin resistance is the root cause of 90% of all instances of diabetes, all of which are classified as Type 2 DM. Untreated, it poses a hazard to civilization since it can lead to terrifying consequences and even death. Oral hypoglycemic medicines presently available act in a variety of ways, targeting various organs and pathways. The use of protein tyrosine phosphatase 1B (PTP1B) inhibitors, on the contrary, is a novel and effective method of controlling type 2 diabetes. PTP1B is a negative insulin signaling pathway regulator; hence, inhibiting PTP1B increases insulin sensitivity, glucose absorption, and energy expenditure. PTP1B inhibitors also restore leptin signaling and are considered a potential obesity target. In this review, we have compiled a summary of the most recent advances in synthetic PTP1B inhibitors from 2015 to 2022 which have scope to be developed as clinical antidiabetic drugs.