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

基本信息

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
项目类别：
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

项目摘要

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 Therapeutics 提出了新型前药的开发和评估疗法作为治疗镰状细胞病（SCD）的一种尚未开发的方法，镰状细胞病是一种涉及单一细胞的遗传性疾病血红蛋白 (Hb) 点突变会导致严重的不良生理并发症，最终导致疼痛最终导致血管闭塞危象、慢性内皮损伤以及进行性终末器官损伤和功能障碍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)糠醛(5-HMF)的衍生物，一种高效的抗镰刀剂，通过变构增加 Hb 氧 (O2) 亲和力来解决 SCD 的根本原因。值得注意的是，该化合物具有在 I 期临床试验（健康成人和 SCD）中具有有效的抗镰状活性和最小的毒性通过相同机制起作用的其他化合物包括香草醛（和衍生物）和 GBT440（Voxelotor，目前处于III期临床试验）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镰化化合物都以醛部分为中心，该醛部分形成具有 Hb α 亚基 N 末端的希夫碱虽然这种必需醛是生物活性的关键，但它也是生物活性的关键。在大多数情况下经历快速的体内代谢，因此，负责限制血浆半- 因此，第一阶段提案的目标是研究许多有前途的候选药物的寿命和生物利用度。确定我们最有效的新型、代谢不稳定的噻唑烷的可行性和治疗潜力 5-HMF 的乙酯前药衍生物已经证明了这种方法具有更持久的潜力。我们初步研究中的体内药代动力学预计将进行研究。帮助获得关键的初步数据，以支持第二阶段更大规模的 IND 支持研究，以实现 SBIR。第一阶段目标，提出了两个具体目标具体目标 1：扩大 3 种前药的化学合成。衍生物和对照（即，MSDD1，未衍生化的天然 5-HMF 噻唑烷乙酯前药）；具体目标 2：评估前药在野生型小鼠体内的 PK/PD 特性，随后评估在 SCD 的 Townes 小鼠模型中最有前途的前药候选者，同时也是这一阶段提案的目标。是为了确定一个具有体内特性和功效的主要 SCD 候选药物来支持 II 期提案，我们预计对前药衍生化的未开发潜力的更全面的了解可能会产生对各种条件下变构 Hb 调节剂的未来发展产生深远影响。