含噻唑环的新型二肽基肽酶IV抑制剂的设计合成及其降血糖作用

目的 合成一类新型的以噻唑环为母体的二肽基肽酶IV (DPP-IV)抑制剂,并测试它们在治疗糖尿病方面的活性。方法 通过Hantzsch噻唑合成反应制备各种2-氨基噻唑,用氯乙酰氯和三乙胺进行氯乙酰化,乙酰化产物经芳基甲胺处理得到相应的仲胺,仲胺在干燥的乙醚中用氯化氢乙醚溶液处理即可得到目标化合物。利用小鼠体内葡萄糖耐受量法测定目标化合物在治疗糖尿病方面的活性。结果 合成了20个结构新颖的化合物,其结构经过¹H-NMR、 ¹³C-NMR、和ESI-MS谱确证。结论 活性测试结果显示,有3个化合物具有明显的降血糖作用,其中化合物6l的活性与阳性对照药格列齐特和格列喹酮相当,另外两化合物6d、6n的 降血糖作用比阳性对照药强,显示出在治疗糖尿病方面的价值。     

二肽基肽酶-4抑制剂研究进展

二肽基肽酶-4抑制剂为一类常用的2型糖尿病治疗药物,可通过抑制二肽基肽酶-4活性延长胰高血糖素样肽-1的作用时间和促进胰岛素分泌,从而降低血糖水平。根据化学结构类型的不同,将二肽基肽酶-4抑制剂分为拟肽类和非拟肽类抑制剂,并分别介绍其药理活性、构效关系及药动学特性等方面的研究进展。     

二肽基肽酶4抑制剂药物相互作用的研究进展

目的:了解二肽基肽酶4(DPP-4)抑制剂药物相互作用的研究进展。方法:查阅近年来国内外相关文献,就DPP-4抑制剂药物相互作用的研究进行归纳和总结。结果与结论:DPP-4抑制剂与大多数药物联用时罕见不良反应发生,无需调整剂量,如二甲双胍、磺脲类、噻唑烷二酮类、格列波糖等传统降糖药,他汀类降脂药,口服避孕药和地高辛等;兰索拉唑、莫沙必利能够增强DPP-4抑制剂的降糖效果;中药辣木提取物和大黄与DPP-4抑制剂存在药物相互作用,能够降低DPP-4抑制剂的疗效,临床联用应谨慎对待;细胞色素P_(450)(CYP)3A4底物或弱效抑制剂辛伐他汀、地尔硫与DPP-4抑制剂联用时无需调整剂量,但与CYP3A4强效抑制剂酮康唑联用时,需按照低剂量给药。尽管DPP-4抑制剂与大多数药物联用具有较好的安全性,但仍需警惕其药物相互作用。     

二肽基肽酶-4抑制剂构效关系研究进展

二肽基肽酶-4(DPP-4)足治疗2型糖尿病的新靶点,强效和选择性DPP-4抑制剂已成为糖尿病治疗新约的开发热点.本文以已上市或进入Ⅲ期临床研究的DPP-4抑制剂为切入点,综述最近几年小分子DPP-4抑制剂的构效关系研究进展.     

二肽基肽酶-4抑制剂治疗糖尿病肾病研究进展

糖尿病肾病(diabetic nephropathy,DN)是糖尿病(diabetes mellitus,DM)最常见的并发症之一,目前临床上以药物治疗为主。口服降糖药物除可优化血糖控制、降低低血糖发生风险外,还可影响DN进展。其中,二肽基肽酶-4抑制剂(dipeptidyl peptidase-4 inhibitor,DPP-4i)是一种在肠促胰岛素系统水平变化中起作用的口服降糖药物。DPP-4i在体外模型中显示出额外的多效性作用,包括减少炎症、纤维化和氧化损伤等,进一步表明其具有潜在的肾脏保护作用。DPP-4i可能有助于延缓DN进展,但尚需进一步研究证明其对肾脏的特异性益处。现就DPP-4i的生物学功能、对DN的作用机制以及临床疗效等进行综述,以期为临床治疗提供新思路。     

二肽基肽酶-4抑制药研究进展

二肽基肽酶-4（DPP-4）抑制药是一类新型口服降糖药,可改善血糖控制,并且不会增加体质量和诱发低血糖,在2型糖尿病的治疗中发挥着越来越重要的作用。本文对DPP-4抑制药作用机制、药动学及临床应用等方面的研究进展进行综述,以期为临床应用提供一定参考。     

二肽基肽酶-4抑制剂在2型糖尿病治疗中的作用

二肽基肽酶-4（DPP-4）抑制剂可选择性抑制DPP-4的活性,阻止胰升糖素样肽-1（GLP-1）裂解失活,提高活性GLP-1的血浆水平,增强其生理作用.该药临床用于治疗2型糖尿病,其能够改善2型糖尿病患者的糖脂代谢、减少β细胞凋亡和促进β细胞增殖,具有降低糖化血红蛋白水平、减少低血糖和副反应发生等作用,在2型糖尿病治疗中有广泛的应用前景.     

二肽基肽酶IV抑制剂与二甲双胍联用的研究进展

二肽基肽酶IV(DPP-4)抑制剂联合二甲双胍能有效控制2型糖尿病(T2DM)患者的血糖,同时明显降低HbA1c水平,且耐受性良好,无体重增加等不良反应,低血糖发生率也较低。本文通过查阅文献介绍了DPP-4抑制剂的作用机制、代表药物以及与二甲双胍联用的优势和现状,综述了DPP-4抑制剂与二甲双胍联合应用在T2DM治疗中的进展。     

新型口服降糖药——二肽基肽酶-Ⅳ抑制剂

胰高血糖素样肽（GLP-1）在调节血糖方面起着重要的作用,但其在体内可迅速被二肽基肽酶-Ⅳ（DPP-Ⅳ）降解失活。DPP-Ⅳ抑制剂可有效抑制GLP-1的降解,通过促进胰岛素分泌、抑制胰高血糖素释放、抑制食欲、减慢胃排空等作用调节血糖,具有不易引起严重低血糖事件、不引起体重增加等特点。本文对GLP-1和DPP-Ⅳ抑制剂的作用特点及已上市使用的西格列汀、维格列汀和沙格列汀的临床疗效、药代动力学以及不良反应等方面进行了综述。     

二肽基肽酶IV抑制剂家族的对比简介

目的介绍二肽基肽酶IV(DPP-4)抑制剂家族药物。方法:通过查阅文献综述DPP-4抑制剂的作用机制、代表药物以及其药动学和药效学区别。结果与结论:DPP-4抑制剂能有效控制2型糖尿病(T2DM)患者的血糖,同时明显降低HbA1c水平,提高GLP-1水平,且耐受性良好,无体重增加等不良反应,低血糖发生率也较低。     

二肽基肽酶Ⅳ抑制剂的研究进展

二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂通过抑制内源性的胰高血糖素样肽-1(GLP-1)的降解,提高GLP-1的水平,进而促进葡萄糖依赖的胰岛素分泌和抑制胰高血糖素产生,从而控制血糖的稳定。DPP-Ⅳ抑制剂具有不影响体重和不增加低血糖风险的优势,在2型糖尿病的治疗中发挥着越来越重要的作用。从结构特点上划分,DPP-Ⅳ抑制剂可分为肽类模拟物和非肽类。本文根据DPP-Ⅳ抑制剂的结构特点对此类抑制剂的最新研究进展进行综述,并对其构效关系进行分析。     

Synthesis, structure-activity relationship, and pharmacophore modeling studies of pyrazole-3-carbohydrazone derivatives as dipeptidyl peptidase IV inhibitors

Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.     

D‐420720, A novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor: structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition

Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP‐1 or GIP administration are short‐lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP‐IV). Therefore, DPP‐IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP‐IV‐specific inhibitor) indicates that DPP‐IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP‐IV inhibitors. Among these compounds, D‐420720 was a potent inhibitor (K_i=39 nM), with a selectivity of 9160‐fold over the DPP‐II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice. Drug Dev Res 69: 514–525, 2008. © 2008 Wiley‐Liss, Inc.     

Inhibition of dipeptidyl peptidase IV activity as a therapy of Type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous, multifunctional, serine protease enzyme and receptor with roles in the control of endocrine and immune function, cell metabolism, growth and adhesion. As an enzyme, DPP IV cleaves the N-terminal dipeptide from the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This inactivates the hormones, thereby cancelling their prandial insulinotropic effect. One approach to restore incretin activity as a therapy for Type 2 diabetes has been the development of DPP IV inhibitors. Inhibitors of DPP IV have shown efficacy and tolerability when used to control the hyperglycaemia of noninsulin-dependent animal models and human Type 2 diabetes. These DPP IV inhibitors prolong active incretin hormone concentrations and may exert additional antidiabetic effects. If long-term clinical trials confirm sustained and safe control of blood glucose, DPP IV inhibitors (known as ‘gliptins’) may be expected to provide a new treatment modality for Type 2 diabetes.     

二肽基肽酶-Ⅳ抑制剂及其构效关系的研究进展

二肽基肽酶-Ⅳ（dipeptidyl peptidase Ⅳ，DPP-4）是经临床证实的治疗2型糖尿病的新靶点，近年来引起制药界的广泛关注。本文综述了几类主要的选择性DPP-4抑制剂及其构效关系的研究进展，特别是利用现有抑制剂-酶复合物晶体x线衍射研究得到的DPP-4结合位点的重要的结构信息，总结出抑制剂-酶紧密结合的重要分子间相互作用，为通过基于结构的药物设计来获得新型选择性DPP-4抑制剂提供依据。     

Inhibition of dipeptidyl peptidase IV by novel inhibitors with pyrazolidine scaffold

Inhibition of dipeptidyl peptidase IV (DPP-IV) activity has been reported to improve nutrient-stimulated insulin secretion through the stabilization of glucagon-like peptide (GLP-1). In the present study, we identified novel DPP-IV inhibitors of pyrazolidine derivatives (Compounds 1 and 2) and characterized their biological effects in vitro and in vivo. Compound 1, an isoleucine pyrazolidide with a phenyl urea group, inhibited rat plasma DPP-IV, porcine kidney DPP-IV, as well as human Caco-2 DPP-IV with IC(50) values of 1.70, 2.26, and 2.02 microM, respectively. Because of the poor pharmacokinetic properties of Compound 1, further optimization was carried out, leading to the discovery of Compound 2, which had similar in vitro activities. Compound 2 acted as a selective and competitive inhibitor of DPP-IV. MALDI-TOF mass spectrometric analysis proved that the compound (20 microM) effectively blocked the degradation of active GLP-1 peptide by 61%. Although similar in in vitro potency, marked improvement of in vivo efficacy and pharmacokinetic properties was seen with Compound 2. Oral administration of Compound 2 resulted in potent and rapid inhibition of circulating DPP-IV in C57BL/6J mice, with ED(50) values of 26mg/kg (s.c.) and 42mg/kg (p.o.). In addition, this compound improved glucose tolerance in ob/ob mice, as determined by an oral glucose tolerance test (OGTT). These results indicate that Compound 2 is a potent and selective DPP-IV inhibitor with oral anti-hyperglycemic activity in vivo.     

Novel N-substituted-2-cyanopyrrolidines as potent inhibitors of dipeptidyl peptidase IV in the treatment of non-insulin-dependent diabetes mellitus

This is the second patent application from Novartis describing N-substituted-2-cyanopyrrolidines as inhibitors of dipeptidyl peptidase IV (DPP-IV). DPP-IV is a serine protease which cleaves Xaa-Pro- or Xaa-Ala- amino terminal sequences from biologically active peptides, transforming them into inactive or even antagonistic species. Among them is glucagon-like peptide 1 (GLP-1), a major stimulator of pancreatic insulin secretion with additional properties in lowering the blood glucose level, which is normally secreted in response to food ingestion. By inhibiting DPP-IV the endogenous GLP-1 is preserved for longer periods, the inhibitors being useful in the treatment of the non-insulin-dependent diabetes mellitus (NIDDM), obesity, arthritis, osteoporosis and other diseases generated or enhanced by impaired glucose tolerance. The compounds claimed in this application are novel N-substituted 2-cyanopyrrolidines bearing adamantyl moieties as biocompatible lipophylic groups; their low nanomolar level of DPP-IV inhibition, as well as their in vivo therapeutic profile, are improved as compared with the results obtained in previous studies.     

二肽基肽酶Ⅳ抑制剂的药理作用及其机制研究

近些年来,二肽基肽酶Ⅳ(dipeptidyl peptidase IV,DPP-IV)抑制剂在治疗2型糖尿病的药物中异军突起,DPP-IV是一种2型多功能跨膜细胞表面糖基化蛋白,在临床治疗和临床试验中,发现了很多DPP-IV抑制剂潜在的药理作用。通过对国内外相关文献的检索,对DPP-IV抑制剂包括降糖、保护心脏、抗炎等药理作用进行了综述。     

Inhibitors of proline-specific dipeptidyl peptidases: DPP IV inhibitors as a novel approach for the treatment of Type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of Type 2 diabetes, with several inhibitors currently in Phase III clinical trials. This review will mainly focus on DPP IV inhibitors that were published in scientific literature and patents after 2002. Medicinal chemistry aspects of several classes of inhibitors are described with respect to inhibitory potency, selectivity over DPP8, DPP9, FAPα and DPP II, stability and ADME/Tox issues. Although the main part of this review is on potent and selective DPP IV inhibitors, selective inhibitors for the related proline-specific dipeptidyl peptidases will be described.