Prodrugs and Derivatives of Hydroxymethylfurfural (5-HMF) to Develop a Novel, Bioavailable Treatment for Sickle Cell Disease

羟甲基糠醛 (5-HMF) 的前药和衍生物可开发镰状细胞病的新型生物利用疗法

• 批准号: 9906825
• 负责人: James Burnett
• 金额: $ 30万
• 依托单位: ILLEXCOR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906825
• 关键词: Acute; Adult; Adult Respiratory Distress Syndrome; Affect; Affinity; Aldehydes; Altitude; American; Animal Testing; Animals; Antisickling Agents; Binding; Bioavailable; Biological; Biological Availability; Biotechnology; Blood; Blood specimen; Cell Survival; Cessation of life; Characteristics; Chemicals; Chronic; Clinical; Complete Blood Count; Control Groups; Data; Development; Disease; Dose; Drug Kinetics; Endothelium; Erythrocytes; Esters; Evaluation; Event; FDA approved; Food; Functional disorder; Future; Gases; Genetic Diseases; Glutamine; Goals; Half-Life; Harvest; Health; Healthcare Systems; Hemoglobin; Hemolysis; Hour; Human; Hypoxia; Immersion; Individual; Inherited; Investigation; Lead; Licensing; Long-Term Effects; Longevity; Masks; Measurement; Measures; Metabolic; Metabolism; Modeling; Modification; Mus; Mutation; Natural Products; Oral; Organ; Organ failure; Outcome; Oxygen; Pain; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Physiological; Plant Roots; Plasma; Prodrugs; Property; Quality of life; Research; Schiff Bases; Series; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Small Business Innovation Research Grant; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Cost; Universities; Validation; Virginia; Wild Type Mouse; chemical synthesis; cost estimate; dosage; drug candidate; efficacy study; histological studies; improved; in vivo; liquid chromatography mass spectrometry; member; mouse model; next generation; novel; novel therapeutics; organ injury; paraform; pharmacokinetics and pharmacodynamics; phase 2 study; polymerization; premature; prevent; scale up; sickling; small molecule; sugar; targeted agent; therapeutic development; vanillin; vaso-occlusive crisis

In this SBIR Phase I project, IllExcor Therapeutics proposes the development and evaluation of novel prodrug therapeutics as a yet untapped approach to treat sickle cell disease (SCD), a hereditary malady involving a single point hemoglobin (Hb) mutation that leads to severe adverse physiological complications culminating in painful vaso-occlusive crises, chronic endothelial damage, and progressive end-organ injury and dysfunction, ultimately leading to premature death. The small molecules proposed for therapeutic development are novel, more potent derivatives of the natural product 5-(Hydroxymethyl)furfural (5-HMF), a highly effective antisickling agent that targets the root cause of SCD by allosterically increasing Hb oxygen (O2) affinity. Notably, this compound has demonstrated potent antisickling activity with minimal toxicity in Phase I clinical trials (healthy adults and SCD patients). Additional compounds acting through the same mechanism include vanillin (and derivatives) and GBT440 (Voxelotor, currently in Phase III clinical trials). However, the biological activity of 5-HMF, its derivatives, and all antisickling compounds acting through this mechanism, centers around an aldehyde moiety that forms a Schiff-base with the N-termini of Hb α-subunits. And while this essential aldehyde is key for bioactivity, it also undergoes rapid in vivo metabolism in most cases, and consequently, is responsible for limiting the plasma half- life and bioavailability of many promising drug candidates. Therefore, the goal of this Phase I proposal is to establish the feasibility and therapeutic potential of the most potent of our novel, metabolically labile thiazolidine ethyl ester prodrug derivatives of 5-HMF. This approach has already demonstrated the potential for more durable in vivo pharmacokinetics in our preliminary studies. The results of the proposed investigation are anticipated to help obtain critical preliminary data to support larger IND-enabling studies in Phase II. To achieve the SBIR Phase I goals, two Specific Aims are proposed. Specific Aim 1: Scale-up chemical synthesis for 3 prodrug derivatives, and a control (i.e., MSDD1, underivatized, native 5-HMF thiazolidine ethyl ester prodrug); and Specific Aim 2: Evaluate the in vivo PK/PD properties of the prodrugs in wild-type mice, and, subsequently, the most promising prodrug candidate in the Townes mouse model of SCD. While the goal of this Phase I proposal is to identify a lead SCD candidate possessing in vivo properties and efficacy to support a Phase II proposal, we anticipate that a more complete understanding of the untapped potential of prodrug derivatization may have a profound impact on the future development of allosteric Hb modifiers for a wide variety of conditions.

在这个SBIR第一阶段项目中，IllExcor Treateutics建议开发和评估新的前药 治疗作为一种尚未开发的方法来治疗镰状细胞病(SCD)，这是一种遗传性疾病，涉及单个 点血红蛋白(Hb)突变，导致严重的不良生理并发症，最终导致疼痛 血管闭塞危机、慢性内皮损伤和进行性终末器官损伤和功能障碍，最终 导致过早死亡。被提议用于治疗开发的小分子是新颖的，更有效的 天然产物5-羟甲基呋喃甲醛(5-HMF)的衍生物，是一种高效的抗感冒剂 通过变构增加Hb氧(O2)亲和力来靶向SCD的根本原因。值得注意的是，这种化合物具有 在I期临床试验(健康成人和SCD)中显示出强大的抗恶心活性和最小的毒性 病人)。通过相同机制作用的其他化合物包括香草醛(及其衍生物)和 GBT440(Voxelotor，目前处于第三阶段临床试验)。然而，5-HMF及其衍生物的生物活性， 所有通过这种机制起作用的抗呕吐化合物，都以醛部分为中心，形成一个 含Hbα-亚基N末端的席夫碱。虽然这种必需的醛是生物活性的关键，但它也 在大多数情况下，在体内经历快速的代谢，因此，负责限制血浆一半- 许多有希望的候选药物的寿命和生物利用度。因此，这一阶段提案的目标是 建立我们最有效的、代谢不稳定的噻唑烷的可行性和治疗潜力 5-羟甲基呋喃的乙酯前药衍生物。这种方法已经证明了更耐用的潜力 体内药代动力学在我们的初步研究中。拟议的调查结果预计将 帮助获得关键的初步数据，以支持在第二阶段进行更大规模的IND支持研究。为实现SBIR 在第一阶段目标中，提出了两个具体目标。具体目标1：3种前体药物的放大化学合成 衍生物和对照药物(即MSDD1，未衍生化的天然5-羟甲基四氢呋喃四氢呋喃甲酯前药)；以及 具体目标2：在野生型小鼠体内评价前药的PK/PD性质，随后， SCD Townes小鼠模型中最有希望的前药候选药物。虽然这项第一阶段提案的目标是 是为了确定一位具有体内特性和有效性的主要SCD候选对象，以支持第二阶段的提议，我们 预计对前体药物衍生化尚未开发的潜力有更全面的了解可能会有 深刻影响着变构HB修饰剂在各种条件下的未来发展。