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（由申请人提供）：大约 2830 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可有效改善胰岛素敏感性，但长期服用会产生明显的副作用，如心血管并发症、肝毒性、脂肪组织堆积、体液潴留、膀胱肿瘤等。我们发现了一种天然存在的类异戊二烯脱落酸 (ABA)，它可以提高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-Like 2 (LANCL2) 是 ABA 的新分子靶标。该项目将评估新型 ABA 衍生物治疗糖尿病的功效和安全性。 STTR一期的具体目标是：（1）生成20种ABA衍生物和类似物，用于开发糖尿病和肥胖相关炎症药物； (2) 进行计算机和体外筛选，选择先导衍生物进行进一步开发； (3) 在两种糖尿病小鼠模型中比较 ABA 衍生药物与吡格列酮（一种已批准的糖尿病药物）的口服疗效。在这项工作结束时，我们的团队将鉴定出两种 ABA 衍生物，它们经过了广泛的体外测试，是安全的，并且在两种糖尿病小鼠模型中已被证明有效。我们将提交至少一项针对 LANCL2 通路的新型抗糖尿病药物的专利申请，其中包含可靠的物质成分声明。拟议的研究将区分 ABA 及其新衍生物与过氧化物酶体增殖物激活受体 g 结合的作用模式 (MOA)。这项工作将为开发基于 ABA 的新型糖尿病治疗方法的可行性提供出色的评估。 STTR II期将优化两种在糖尿病小鼠模型中显示出功效的先导化合物，并沿着监管途径推进它们，包括功效、作用方式、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，致力于提交研究性新药申请以准备人体临床试验所需的测试。为了优化口服药物递送，我们将开发更多具有指南范围内的分子特性（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；并测试其功效和安全性。长期目标：生物治疗 (BTI) 技术的目标是为现有糖尿病治疗提供一种口服治疗替代方案，成本更低，疗效更好，同时减少不良副作用。该技术将解决糖尿病患者面临的健康问题，并将为美国 2830 万市场提供巨大的商业潜力，估计每年仅处方药费用就超过 125 亿美元。