预约演示

更新于：2025-05-07

GPR119

更新于：2025-05-07

基本信息

别名

G protein-coupled receptor 119、G-protein coupled receptor 119、Glucose-dependent insulinotropic receptor

+ [3]

简介

Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway.

关联

项与 GPR119 相关的药物

DA-1241

靶点

GPR119

作用机制

GPR119激动剂

在研机构

MetaVia, Inc. [+1]

原研机构

Dong-A Pharmaceutical Co., Ltd.

在研适应症

2型糖尿病 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

GSK1104252A

靶点

GPR119

作用机制

GPR119激动剂

在研机构

GlaxoSmithKline, Inc.

原研机构

GlaxoSmithKline, Inc.

在研适应症

2型糖尿病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

GPR119 agonists(Hyundai)

靶点

GPR119

作用机制

GPR119激动剂

在研机构

Hyundai Pharmaceutical Co., Ltd.

原研机构

Hyundai Pharmaceutical Co., Ltd.

在研适应症

2型糖尿病 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 GPR119 相关的临床试验

NCT06054815

/ Completed临床2期

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel, Phase 2a Clinical Trial to Evaluate the Efficacy and Safety of DA-1241 in Subjects With Presumed Non-alcoholic Steatohepatitis (NASH)

A multicenter, randomized, double-blind, placebo-controlled, parallel, Phase 2a clinical trial to evaluate the efficacy and safety of DA 1241 in subjects with presumed non-alcoholic steatohepatitis (NASH).

开始日期2023-09-14

申办/合作机构

MetaVia, Inc.

CTRI/2021/09/036637

/ Not yet recruiting临床1期

A Phase 1, double-blind, randomized, placebo controlled, Parallel study to assess the safety, tolerability and pharmacokinetics of single and multiple doses of MKP 10241 Suspension administered orally in healthy adult, human, male subjects.

开始日期2021-09-20

申办/合作机构

Mankind Pharma Ltd.

NCT03646721

/ Completed临床1期

A Phase 1b, Double-Blind, Placebo-Controlled, Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability, PK and PD of DA-1241 in Healthy Male Subjects and Subjects With T2DM

This is a double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK and PD of DA-1241 in healthy male subjects and subjects with T2DM

开始日期2018-08-29

申办/合作机构

Dong-A ST Co., Ltd.

100 项与 GPR119 相关的临床结果

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100 项与 GPR119 相关的转化医学

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0 项与 GPR119 相关的专利（医药）

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309

项与 GPR119 相关的文献（医药）

2025-05-01·International Immunopharmacology

Oleoylethanolamide ameliorates collagen-induced rheumatoid arthritis via activation of GPR119

Article

作者: Im, Dong-Soon ; Lee, Jung-Eun

Lower levels of oleoylethanolamide (OEA) have been observed in the synovial fluids of patients with rheumatoid arthritis and osteoarthritis compared to healthy controls. OEA is known as an anti-inflammatory lipid and acts as an endogenous ligand for GPR119. This study investigated the functional roles of GPR119 using a murine collagen-induced arthritis (CIA) model. The effects of OEA and AR231453, a selective synthetic GPR119 agonist, were tested on the CIA model in Gpr119 wild-type (WT) and deficient DBA-1 J mice. In the CIA model, administration of OEA or AR231453 reduced arthritis scores, foot thickness, loss of proteoglycan, and bone erosion in Gpr119 WT mice, but not in Gpr119-deficient mice. Treatment with OEA or AR231453 significantly suppressed the CIA-induced increase in pro-inflammatory cytokine expression in the feet and IgG levels in the serum, and rebalanced Th1/Th17 and Treg cells in the spleens of Gpr119 WT mice, but not in Gpr119-deficient mice. Additionally, OEA and AR231453 suppressed mRNA expression levels of inflammatory cytokines in human SW982 synovial cells. Both compounds also suppressed Th1/17 cell differentiation and enhanced Treg differentiation in splenocytes from Gpr119 WT mice, but not in Gpr119 knockout mice. These findings suggest that GPR119 activation may serve as a therapeutic strategy for rheumatoid arthritis by regulating Th1/Th17/Treg cell differentiation and rebalancing Th1/Th17 and Treg cells.

2025-03-01·Cell Proliferation

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β‐cell function in NAFPD by inhibiting MST1‐Foxo3a signalling pathway

Article

作者: Zhang, Chenglei ; Ren, Yanru ; Li, Jiarui ; Li, Xin ; Li, Jianning ; Ma, Jie ; Wang, Lijuan ; Song, Hui ; Yang, Yanhui ; Wu, Yuanyuan ; Yang, Yi

AbstractGPR119 agonists are being developed to safeguard the function of pancreatic β‐cells, especially in the context of non‐alcoholic fatty pancreas disease (NAFPD) that is closely associated with β‐cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β‐cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119−/− mice fed with a high‐fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β‐cell function via the MST1‐Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β‐cell function in NAFPD mice. It inhibited the upregulation of MST1‐Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β‐cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β‐cell function in NAFPD mice and abolished its inhibitory effect on the MST1‐Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β‐cells, enhancing mitophagy and alleviating β‐cell dysfunction in the context of NAFPD by suppressing the MST1‐Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.

2025-03-01·International Immunopharmacology

Oleoylethanolamide ameliorates allergic asthma and atopic dermatitis via activation of GPR119

Article

作者: Lee, Jung-Eun ; Im, Dong-Soon

Serum levels of oleoylethanolamide (OEA) have been associated with the severity of pulmonary diseases, and augmented levels of epidermal OEA have been observed in response to low-grade inflammation in human skin. OEA acts as an endogenous ligand for GPR119; thus, the functional roles of GPR119 were investigated using two murine models. We tested effects of OEA and AR231453, a selective synthetic GPR119 agonist on ovalbumin (OVA)-induced allergic asthma and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like models in GPR119 wild-type (WT) and deficient mice. In OVA-induced allergic asthma model, administration of OEA or AR231453 reduced allergic feature, including airway hyperresponsiveness, eosinophil accumulation in bronchoalveolar lavage fluid, airway inflammation, and mucin secretion in the lungs, and both ameliorated DNCB-induced atopic dermatitis-like skin lesions, such as hypertrophy and mast cell accumulation, in GPR119 wild-type (WT) mice, but not in GPR119-deficient mice. OEA or AR231453 treatment reduced OVA-induced increase in pro-inflammatory cytokine expression, and type 2 innate lymphoid cells in the lungs, and both significantly suppressed the DNCB-induced lymph node enlargement and inflammatory Th2/1/17 cells in GPR119 WT mice, but not in GPR119-deficient mice. In RBL-2H3 mast cells, OEA or AR231453 suppressed degranulation and Th2 cytokine expression. These findings suggest that OEA functions to protect against allergic asthma and atopic dermatitis via GPR119 activation by suppressing immune responses in the lungs, lymph nodes, and skin, highlighting GPR119 activation as a therapeutic target for allergic and inflammatory diseases.

项与 GPR119 相关的新闻（医药）

2025-04-23

·PRNewswire

MetaVia Announces Late-Breaking Poster Presentation on DA-1241 at the EASL Congress 2025

CAMBRIDGE, Mass., April 23, 2025 /PRNewswire/ -- MetaVia Inc. (Nasdaq: MTVA), a clinical-stage biotechnology company focused on transforming cardiometabolic diseases, today announced that an abstract highlighting data from its Phase 2a clinical trial of DA-1241, a novel G-Protein-Coupled Receptor 119 (GPR119) agonist, in patients with presumed metabolic dysfunction-associated steatohepatitis (MASH), has been accepted as a late-breaking poster presentation at the European Association for the Study of the Liver (EASL) Congress 2025, taking place May 7-10, 2025 in Amsterdam, the Netherlands. Title: DA-1241, a GPR119 Agonist, Demonstrates Hepatoprotective and Glucose-Regulating Effects in a 16-week Randomized Placebo-Controlled Trial in Presumed Metabolic Dysfunction-Associated Steatohepatitis (MASH) Patients Presenting Author: Rohit Loomba, MD, MHSc, Professor of Medicine in the Division of Gastroenterology, and Adjunct Professor in the Division of Epidemiology at University of California, San Diego. Abstract Number: LB2517 Final Abstract ID: LBP-005 Session: Late Breaker Posters Session Date: May 7-10, 2025 Presentation Start: May 7, 2025, 8:30 am CET A copy of the poster will be available on the Posters section of the MetaVia website after the presentation. About DA-1241 DA-1241 is a novel G-Protein-Coupled Receptor 119 (GPR119) agonist with development optionality as a standalone and/or combination therapy for both MASH and type 2 diabetes (T2D). Agonism of GPR119 in the gut promotes the release of key gut peptides GLP-1, GIP, and PYY. These peptides play a further role in glucose metabolism, lipid metabolism and weight loss. DA-1241 has beneficial effects on glucose, lipid profile and liver inflammation, supported by potential efficacy demonstrated during in vivo preclinical studies. The therapeutic potential of DA-1241 has been demonstrated in multiple pre-clinical animal models of MASH and T2D where DA-1241 reduced hepatic steatosis, inflammation, fibrosis, and improved glucose control. Furthermore, in Phase 1a, 1b and 2a trials, DA-1241 was well tolerated in both healthy volunteers and those with T2DM. In a Phase 2a clinical study, DA-1241 demonstrated direct hepatic action in addition to its glucose lowering effects. About MetaVia MetaVia Inc. is a clinical-stage biotechnology company focused on transforming cardiometabolic diseases. The company is currently developing DA-1726 for the treatment of obesity and is developing DA-1241 for the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH). DA-1726 is a novel oxyntomodulin (OXM) analogue that functions as a glucagon-like peptide-1 receptor (GLP1R) and glucagon receptor (GCGR) dual agonist. OXM is a naturally-occurring gut hormone that activates GLP1R and GCGR, thereby decreasing food intake while increasing energy expenditure, thus potentially resulting in superior body weight loss compared to selective GLP1R agonists. DA-1241 is a novel G-protein-coupled receptor 119 (GPR119) agonist that promotes the release of key gut peptides GLP-1, GIP, and PYY. In pre-clinical studies, DA-1241 demonstrated a positive effect on liver inflammation, lipid metabolism, weight loss, and glucose metabolism, reducing hepatic steatosis, hepatic inflammation, and liver fibrosis, while also improving glucose control. In a Phase 2a clinical study, DA-1241 demonstrated direct hepatic action in addition to its glucose lowering effects. For more information, please visit . Contacts: MetaVia Marshall H. Woodworth Chief Financial Officer +1-857-299-1033 [email protected] Rx Communications Group Michael Miller +1-917-633-6086 [email protected] SOURCE MetaVia Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床2期临床结果临床1期

2024-12-14

·药时代

最新成果|PNAS|徐华强/吴灿荣团队揭示前列腺素D2受体DP2的分子机制

前列腺素是通过环氧合酶（COX）途径合成的生物活性脂质，在炎症、免疫反应和多种细胞过程中发挥着重要作用。它们通过与特定的脂质G蛋白偶联受体相互作用，诱发多种生物功能，包括前列腺素D2受体DP1和DP2、前列环素受体IP、前列腺素E2受体EP1至EP4、前列腺素F2α受体FP以及血栓素受体TP。前列腺素D2（PGD2）主要在中枢神经系统和免疫系统中产生，并在睡眠调节和炎症反应中发挥重要作用。DP2，也被称为T辅助细胞2型表达的趋化因子受体同源分子（CRTH2），在过敏性疾病中尤为重要。尽管DP2与其他前列腺素受体的序列同源性较低，但它与趋化因子受体的关系密切，主要在T辅助细胞2型、嗜酸性粒细胞等免疫细胞中表达。DP2受体通过与Gi亚型G蛋白偶联，调节cAMP和Ca2+的水平，并能与β-arrestin蛋白相互作用。研究团队发现，PGD2主要通过Gαi信号通路激活DP2，而吲哚美辛则倾向于通过β-arrestin蛋白信号通路进行激活 (图1A-C)。利用冷冻电子显微镜（cryo-EM）技术，团队成功解析了三种DP2-Gi复合物的结构，包括未结合配体的DP2-Gi复合物、结合内源性配体PGD2的复合物，以及结合吲哚美辛的复合物（图1D-F）。这些结构揭示了PGD2与吲哚美辛在DP2上的不同结合模式，为理解受体激活和信号转导提供了关键见解（图1G）。通过结构分析结合功能实验，研究深入探讨了这两种分子独特的受体激活机制，并揭示了吲哚美辛偏向性激活β-逮捕蛋白的分子机制（图1H-J）。此外，研究还发现了一个新的磷脂结合位点，该位点位于DP2与G蛋白的交互界面。结合质谱分析、G蛋白招募实验、AlphaScreen结合力测定以及分子动力学模拟，研究表明该磷脂类在调节DP2信号转导中发挥了重要作用 (图1K-N)。这一发现不仅丰富了对DP2功能的理解，也为未来的药物开发提供了新的思路。图1. (A) 吲哚美辛和PGD2的化学结构。(B) 吲哚美辛和PGD2对DP2激活的pEC50值。(C) 人DP2受体信号偏向的示意图。(D, E, F) PGD2-DP2-Gi复合物、吲哚美辛-DP2-Gi复合物和DP2-Gi复合物的冷冻电镜密度图。(G) PGD2、吲哚美辛和W2596.48之间的距离测量。(H) 吲哚美辛、fevipiprant及参与受体激活的关键残基的位置。(I) 吲哚美辛结合的DP2中吲哚美辛与非活性DP2中F2947.43之间的冲突。(J) 吲哚美辛结合的DP2与非活性DP2的叠加，二者在TM6和TM7的中点对齐；突出显示了吲哚美辛结合的DP2中的N296与非活性DP2中TM6骨架之间的冲突。(K) DP2-Gi与16:0-18:1 PI之间的相互作用界面；残基以棒状表示。(L) 质谱分析结果。(M) 野生型DP2与突变体之间Gi招募效率的比较。(N) AlphaScreen相互作用测定结果，显示在不同磷脂存在下，10 nM纯化的生物素-Gi与10 nM H8标记的DP2蛋白的招募。该团队此前已报道前列腺素F2α（Nature Communications, 2023）和前列环素受体（Science Advances, 2024）的结构药理学机制，当前研究是在前列腺素受体结构药理学领域的又一重要突破。研究团队希望通过进一步探索，推动DP2相关药物的临床应用，为过敏性疾病患者带来新的治疗选择。随着对DP2机制的深入了解，科学家们期待能够设计出更具针对性和安全性的抗过敏性哮喘药物，从而改善患者的生活质量。本研究中的冷冻电镜数据在上海市高峰电镜中心收集。上海科技大学的徐久银、上海药物研究所的徐有伟副研究员、南京中医药大学的博士生侯丽和上海药物研究所博士生何欣恒为该论文的共同第一作者；上海药物所的徐华强研究员和吴灿荣副研究员为共同通讯作者。上海药物所为本研究的第一完成单位。清华大学瑕瑜教授和临港实验室蒋轶研究员对此研究做出了重要贡献。该工作获得了国家自然科学基金委、科技部、中科院先导专项以及上海市市级科技重大专项等项目的资助。 Nature Reviews Endocrinology 综述丨徐华强/段佳团队概述冷冻电镜在GPCR药物发现中的突破性研究 Nature |上海药物所徐华强课题组与合作者共同揭示“冰毒”与其受体TAAR1的分子识别机制 Cell Research | 徐华强团队合作揭示多巴胺受体系统介导药物分子多重药理学活性的结构基础 Nat Chem Bio | 上海药物研究所庄友文/徐华强揭示过敏毒素识别补体受体系统的分子模式和选择性机理 NSMB | 徐华强/谢欣/蒋轶发现孤儿受体GPR119内源性配体的分子机制首发 | 中科院徐华强/尹万超团队联合攻关新冠病毒奥密克戎（Omicron）变异株刺突蛋白及其与受体和抗病毒抗体的复合物结构点击这里，查看更多精彩！

2024-11-14

·奇点网

改变肠道菌群组成，可改善AD病理。

*仅供医学专业人士阅读参考我们知道，β-淀粉样蛋白（Aβ）沉积是阿尔茨海默病（AD）的主要病理特征之一。近年来，越来越多的研究显示，肠道菌群失调与Aβ沉积有关。因此，能否通过改变肠道菌群的组成来改善AD病理，成为了很多科学家们研究的重点。近期，首都医科大学基础医学院张晨/王伟/刘希成团队发表了一篇重要研究成果。他们发现，以梭菌属（Clostridium）丰度增加和拟杆菌属（Bacteroides）丰度减少为特征的肠道菌群失调与Aβ沉积密切相关。而通过补充卵形拟杆菌或其相关代谢物溶血磷脂酰胆碱（LPC），则可以显著减少AD小鼠大脑Aβ斑块的形成，并改善认知障碍。机制上，研究人员发现，LPC主要通过激活孤儿受体GPR119，下调了铁死亡关键基因ACSL4的表达，从而有效抑制了铁死亡，并改善了AD病理。研究发表在《细胞·代谢》上[1]。论文首页截图通过使用广谱抗生素清除AD小鼠的肠道菌群，研究人员观察到，抗生素引起的肠道菌群改变会导致AD小鼠大脑Aβ沉积减少。而将野生小鼠粪便菌群移植到AD小鼠体内，也可减少AD小鼠大脑Aβ沉积。这提示，肠道菌群的变化与Aβ沉积之间存在密切关系。进一步，利用粪便纳米孔元基因组测序分析，研究人员观察了AD小鼠和野生小鼠肠道菌群的差异。结果发现，与野生小鼠相比，AD小鼠的肠道菌群出现了明显的改变，主要表现为梭菌属（如巴氏梭菌、拜氏梭菌、无害梭菌）丰度的增加和拟杆菌属（如卵形拟杆菌、多氏拟杆菌、普通拟杆菌）的丰度减少。AD小鼠肠道菌群失调特征以上结果表明，以梭菌属丰度增加和拟杆菌属丰度减少为特征的肠道菌群失调与Aβ沉积密切相关。接下来，研究人员分别给经抗生素处理的AD小鼠接种了卵形拟杆菌和/或拜氏梭菌，结果发现接种拜氏梭菌会影响卵形拟杆菌的定植，这也意味着这两种菌属之间存在竞争关系。而通过单独补充不同种类的梭菌和拟杆菌，研究人员发现，大部分梭菌都会促进AD小鼠大脑中的Aβ沉积，而大部分拟杆菌则可以显著减少AD小鼠大脑中的Aβ沉积，其中卵形拟杆菌在减少Aβ斑块方面的效果最为显著。卵形拟杆菌减少Aβ斑块沉积鉴于肠道菌群相关代谢产物也可能会通过肠－脑轴来影响大脑功能，研究人员通过进一步实验发现，补充卵形拟杆菌或其相关代谢产物LPC（在多个代谢产物中，只有LPC与拟杆菌属丰度呈正相关，与梭菌属丰度呈负相关），不仅可以减少Aβ斑块沉积，挽救突触功能，还能减少胶质增生和减轻髓鞘变性，改善认知障碍。LPC改善AD病理随后，研究人员还探究了LPC影响AD病理的相关机制。结果发现，LPC主要通过激活孤儿受体GPR119，下调了铁死亡关键基因ACSL4的表达，从而有效抑制了铁死亡，并改善了AD病理。LPC抑制铁死亡最后，通过对AD患者粪便和血清样本的分析，研究人员发现，与AD小鼠一样，AD患者粪便中也存在拟杆菌属丰度和血清LPC水平降低的现象，这也提示，该研究结果存在一定的临床转化价值。综上，该研究不仅揭示了肠道菌群与AD病理之间的联系，还发现了一种由肠道菌群激发的调节AD病理的新路径（即LPC-GPR119-铁死亡信号路径）。这一发现也为开发新的AD治疗策略提供了重要的科学依据。参考链接：[1]Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis.CellMetabolism (2024). DOI: 10.1016/j.cmet.2024.10.006本文作者｜张金旭

微生物疗法临床研究孤儿药