Development of Novel LANCL2-based Anti-diabetic Compounds

基于 LANCL2 的新型抗糖尿病化合物的开发

• 批准号: 8644667
• 负责人: Josep Bassaganya-Riera
• 金额: $ 18.83万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644667
• 关键词: Abscisic Acid; Address; Adipocytes; Adipose tissue; Adult; Adverse effects; Affinity; American; Antidiabetic Drugs; Area; Atherosclerosis; Binding; Biochemistry; Biological Response Modifier Therapy; Bladder Neoplasm; Brain; Calorimetry; Cardiovascular system; Chronic; Clinical Trials; Computer Simulation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Drug Delivery Systems; Drug Targeting; Endocrinologist; Endothelial Cells; Excretory function; Family suidae; Follow-Up Studies; GTP-Binding Proteins; Goals; Growth; Guidelines; Health; Health Benefit; Heart; Hepatotoxicity; Human; Hydrogen Bonding; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory disease of the intestine; Insulin Resistance; Intellectual Property; Investigational New Drug Application; Kidney; Knowledge; Lead; Legal patent; Letters; Licensing; Ligand Binding Domain; Ligase; Liquid substance; Lung; Mammals; Marketing; Mediating; Metabolic Diseases; Metabolism; Methods; Molecular; Molecular Models; Molecular Target; Molecular Weight; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Oral; Oral Administration; Overweight; Pancreas; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pioglitazone; Plants; Positioning Attribute; Prediabetes syndrome; Preparation; Property; Publishing; Rattus; Regulatory Pathway; Research; Role; Safety; Signal Pathway; Signal Transduction; Small Business Technology Transfer Research; Solid; Stem cells; Structure of beta Cell of islet; Surface; Takeda brand of pioglitazone hydrochloride; Technology; Testing; Therapeutic; Tissues; Titrations; Toxic effect; Toxicokinetics; Treatment Cost; Treatment Efficacy; Virginia; Work; absorption; analog; base; biological adaptation to stress; commercial application; commercialization; cost; db/db mouse; design; diabetic; experience; follow-up; impaired glucose tolerance; improved; in vitro testing; insulin secretion; insulin sensitivity; insulin sensitizing drugs; isoprenoid; lanthionine; middle age; molecular modeling; mouse model; new therapeutic target; novel; prevent; public health relevance; receptor; regenerative; research and development; response; safety study; screening; technological innovation

DESCRIPTION (provided by applicant): About 28.3 million Americans have type II diabetes (T2D) and over 40.1% of middle-aged adults have prediabetes, a condition characterized by impaired glucose tolerance and insulin resistance. Current antidiabetic medications are effective in improving insulin sensitivity, but their chronic administration has significant side effects suc as cardiovascular complications, hepatotoxicity, adipose tissue accumulation, and fluid retention, bladder tumors. We have discovered a naturally occurring isoprenoid, abscisic acid (ABA) that increases insulin sensitivity and suppresses inflammation in overweight and obesity. Recently, we have identified Lanthionine Synthetase Component C-Like 2 (LANCL2) as a novel molecular target for ABA. This project will evaluate the efficacy and safety of novel ABA derivatives for treating diabetes. The specific aims for the proposed STTR Phase I are: (1) To generate 20 derivatives and analogs of ABA for development of diabetes and obesity-related inflammation drugs; (2) To perform in silico and in vitro screening to select lead derivatives for further development; and (3) To compare the oral efficacy of ABA-derived drugs against pioglitazone, an approved diabetes drug, in two mouse models of diabetes. At the conclusion of this effort our team will have identified two derivatives of ABA that have undergone extensive in vitro testing and are safe and with proven efficacy in two mouse models of diabetes. We will have filed at least one patent application with robust composition of matter claims for the new class of anti-diabetic drugs that target the LANCL2 pathway. The proposed studies will differentiate the mode of action (MOA) of ABA and its new derivatives from binding to peroxisome proliferator-activated receptor g. This work will provide an excellent assessment of the feasibility of developing novel ABA-based treatments for diabetes. STTR Phase II will optimize two of the lead compounds with demonstrated efficacy in mouse models of diabetes and advance them along the regulatory pathway, including efficacy, mode of action, absorption, distribution, metabolism and excretion, phamacokinetics/pharmacodynamics, toxicokinetics analysis and toxicity assessment working towards the testing required to submit an investigational new drug application in preparation for human clinical trials. To optimize oral drug delivery we shall develop more analogs that have molecular properties (ClogP, molecular weight, polar surface area, numbers of rings, rotable bonds, N and O atoms, hydrogen bond donors and acceptors) within the guidelines; and test their efficacy and safety. Long Term Goal: The goal of BioTherapeutics (BTI) technology will be to provide an oral therapeutic alternative to existing diabetes treatments that costs less and provides greater efficacy with reduced adverse side effects. The technology will address the overlying health problem with patients suffering with diabetes and will provide a significant commercialization potential to a market of 28.3 million estimated to be over $12.5 Billion for prescription medication costs alone annually in the US.

描述(申请人提供)：大约2,830万美国人患有II型糖尿病(T2D)，超过40.1%的中年成年人患有糖尿病前期，这是一种以糖耐量受损和胰岛素抵抗为特征的疾病。目前的抗糖尿病药物在改善胰岛素敏感性方面是有效的，但它们的长期应用有明显的副作用，如心血管并发症、肝毒性、脂肪组织积聚、液体滞留和膀胱肿瘤。我们已经发现了一种天然存在的异戊二烯类脱落酸(ABA)，它可以增加胰岛素敏感性，并抑制超重和肥胖患者的炎症。最近，我们发现羊毛硫氨酸合成酶成分C-样2(LANCL2)是ABA的一个新的分子靶点。本项目将评估新型ABA衍生物治疗糖尿病的有效性和安全性。拟议的STTR第一阶段的具体目标是：(1)产生20种ABA的衍生物和类似物，用于开发糖尿病和肥胖相关的炎症药物；(2)进行电子计算机和体外筛选，选择用于进一步开发的先导化合物；以及(3)在两种糖尿病小鼠模型上比较ABA衍生药物与已获批准的糖尿病药物吡格列酮的口服疗效。在这项工作结束时，我们的团队将确定两种ABA的衍生物，它们已经经过了广泛的体外测试，并且在两种糖尿病小鼠模型中是安全的，并且被证明是有效的。我们将至少提交一项针对LANCL2途径的新型抗糖尿病药物的专利申请，其中包含稳健的物质组成权利主张。建议的研究将区分ABA及其新的衍生物与过氧化物酶体增殖物激活受体g的结合的作用模式。这项工作将为开发基于ABA的糖尿病新疗法的可行性提供极好的评估。STTR第二阶段将优化两种在糖尿病小鼠模型中被证明有效的先导化合物，并沿着调节途径推进它们，包括有效性、作用模式、吸收、分布、代谢和排泄、药代动力学/药效学、毒代动力学分析和毒性评估，努力进行提交研究性新药申请所需的测试，为人类临床试验做准备。为了优化口服给药，我们将在指南范围内开发更多具有分子性质(ClogP、分子量、极性表面积、环数、可旋转键、N和O原子、氢键供体和受体)的类似物，并测试它们的有效性和安全性。长期目标：生物治疗(BTI)技术的目标将是为现有的糖尿病治疗提供一种口服治疗的替代品，这种治疗方法成本更低，疗效更好，副作用更少。这项技术将解决糖尿病患者的严重健康问题，并将为2830万人的市场提供巨大的商业潜力，据估计，仅在美国每年仅处方药成本就超过125亿美元。