Second generation GLP-1 agonists without nausea/emesis side effects

第二代 GLP-1 激动剂，无恶心/呕吐副作用

• 批准号: 10183954
• 负责人: Bart C DE JONGHE
• 金额: $ 62.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183954
• 关键词: Acute; Agonist; Amaze; Anatomy; Animals; Attention; Automobile Driving; Behavior; Behavioral; Beta Cell; Binding; Binding Proteins; Blood; Blood Glucose; Body Weight; Body Weight decreased; Brain; Brain Stem; Cachexia; Carrier Proteins; Cell Line; Chemicals; Chronic; Clinical; Complex; Data; Diabetes Mellitus; Diagnosis; Disease; Dorsal; Dose; Drug Kinetics; Eating; Economic Burden; Emetics; Epidemic; Event; FDA approved; Family; GCG gene; GLP-I receptor; Gastric Emptying; Generations; Glucagon; Glucose tolerance test; Health Care Costs; Hormones; Human; Hyperglycemia; Hypoglycemia; Hypothalamic structure; In Vitro; Incidence; Insulin; Intake; Intestines; Intracellular Transport; Intrinsic factor; Kaolin; Life; Ligands; Malaise; Mammals; Mediating; Mediator of activation protein; Medical; Medical Economics; Modeling; Mus; Nausea; Nausea and Vomiting; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacopoeias; Pharmacotherapy; Physiological; Population; Prognosis; Public Health; Publishing; Quality of life; Rattus; Reporting; Research; Rodent Model; Role; Shrews; Sick Role; Site; Testing; Therapeutic; Therapeutic Effect; Thinness; Tissues; Transcobalamins; Vagus nerve structure; Vitamin B 12; Vomiting; analog; base; cobinamide; comorbidity; compliance behavior; design; diet-induced obesity; economic cost; exenatide; experience; experimental study; glucagon-like peptide 1; glycemic control; improved; in vivo; incretin hormone; inhibitor/antagonist; innovation; insulin secretion; mouse model; novel; pancreatic juice; pre-clinical; pre-clinical assessment; reduced food intake; side effect; subcutaneous; therapeutic evaluation; virtual

Project Summary The proposed research of this R01 application focuses on creating a second-generation glucagon-like peptide- 1 (GLP-1)-based pharmaceutical that retains all of the blood glucose lowering profiles but completely eliminates the major side effects of nausea, vomiting and malaise. Such side effects, along with hypophagia, are produced by existing GLP-1R agonists due to central nervous system (CNS) penetrance and direct action in the brain. Thus, we sought to create GLP-1R agonists with reduced brain penetrance but with the full potent pharmacodynamic profile on pancreatic GLP-1R populations. Our novel preliminary data convincingly demonstrate the ability of a vitamin B12 (B12) conjugate of the GLP1-R agonist Exendin-4 (Ex4), namely (B12- Ex4), to produce hypoglycemia in a glucose tolerance test (GTT) in both mouse and rat models without producing hypophagia or nausea/malaise. This glucoregulation without nausea/malaise appears to be due to a virtual absence of ligand penetrance into the CNS, a hypothesis supported by radiolabelled B12 studies showing extremely low levels of B12 entry into the brain, as well as immunohistochemical analyses of fluorescently- tagged B12-Ex4 in comparison to native Ex4 at the site of CNS activation. This application therefore tests the following specific aims to both enhance the preclinical assessment of B12-Ex4 as a second-generation T2DM therapeutic and test the hypothesis that the total portfolio of therapeutic effects that exploit the `B12-family' can be enhanced by conjugation of Ex4 to a fragment of B12, specifically cobinamide (Cbi), which targets Haptocorrin (HC), a Cbi binding protein found only in mammals, including humans: [1] Characterizes the physiological, behavioral and anatomical mechanisms mediating the hypoglycemic effects of B12-Ex4 without the incidence of hypophagia and nausea/malaise using both lean/euglycemic and obese/hyperglycemic rat and mouse models; [2] Conducts systematic in vitro and in vivo analyses of a novel Cbi-Ex4 compound for glucoregulation without eliciting nausea/emesis or competing with endogenous B12 transport in the musk shrew which both is capable of emesis and expresses HC, like the human, but unlike the mouse and rat. The compounds described herein also offer scope to investigate, through relatively simple experimentation, the role of CNS versus periphery in the function of GLP-1R agonists in animals and humans. As such they have significant potential as investigative research probes in addition to their clear potential as a new generation of therapeutics. Most notably, these highly innovative experiments will provide the necessary pre-clinical analyses for the B12- and/or Cbi-based conjugates of Ex4. Such studies will lead to significantly improved, clinically beneficial, second generation therapeutics for the treatment of T2DM without the most common nausea/malaise side effects of existing GLP- 1-based therapeutics, which will improve patient quality of life, patient compliance to therapy, and expand the population that can benefit from the amazing improved glycemic profile achieved with GLP-1R agonists.

项目摘要 该R01应用的拟议研究重点是创建第二代胰高血糖素样肽 - 1（GLP-1）的药物保留所有血糖降低谱但完全消除 恶心，呕吐和不适的主要副作用。产生这种副作用，以及下降 通过现有的GLP-1R激动剂，由于中枢神经系统（CNS）的渗透性和在大脑中的直接作用。 因此，我们试图创造出脑部渗透率降低但充分有效的GLP-1R激动剂 胰腺GLP-1R种群的药效学概况。我们小说的初步数据令人信服 证明GLP1-R激动剂Exendin-4（EX4）的维生素B12（B12）结合物的能力（B12-- Ex4），在小鼠和大鼠模型中的葡萄糖耐量测试（GTT）中产生低血糖 低脂或恶心/不适。这种没有恶心/不适的葡萄糖调节似乎是由于虚拟的 在CNS中没有配体渗透性，这是由放射性标记的B12研究支持的假设 B12的极低水平进入大脑，以及荧光的免疫组织化学分析 与CNS激活部位的本机EX4相比，标记为B12-EX4。因此，此应用程序测试了 遵循特定的目的是增强B12-EX4作为第二代T2DM的临床前评估 治疗和检验的假设是，利用“ B12-家庭”的治疗效应的总组合可以 通过将EX4结合到B12的片段，特别是核氧化酰胺（CBI）来增强 （HC），仅在包括人在内的哺乳动物中发现的CBI结合蛋白：[1]表征生理学， 行为和解剖机制介导了B12-EX4的降血糖作用，而没有发生 使用瘦/e糖/肥胖/高血糖大鼠和小鼠模型的低脂和恶心/不适； [2]对新型CBI-EX4化合物进行系统的体外和体内分析，用于葡萄糖调节 引起恶心/呕吐或与麝香中的内源性B12转运竞争，这两者都有能力 像人类一样，像人类一样表达HC，但与小鼠和大鼠不同。本文描述的化合物 还提供了通过相对简单的实验调查中枢神经系统与外围的作用的范围 GLP-1R激动剂在动物和人类中的功能。因此，它们作为调查具有巨大的潜力 研究探查除了它们作为新一代治疗剂的明显潜力外。最值得注意的是这些 高度创新的实验将为基于B12和/或CBI提供必要的临床前分析 EX4的共轭。这样的研究将导致显着改善，临床上有益，第二代 治疗T2DM的治疗剂，而没有现有GLP的最常见恶心/不适的副作用 1个基于1的治疗方法，可以提高患者的生活质量，患者对治疗的依从性并扩大 可以从GLP-1R激动剂实现的惊人改善血糖概况中受益的人群。