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SBIR I期项目中，IllExcor Therapeutics提出了新型前药的开发和评估 镰状细胞病（SCD）是一种遗传性疾病， 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 血管闭塞危象、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。用于治疗开发的小分子是新颖的， 天然产物5-（羟甲基）糠醛（5-HMF）的衍生物，一种高效的抗氧化剂， 通过变构增加Hb氧（O2）亲和力，靶向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）中显示出有效的抗镰状细胞活性，具有最小的毒性 患者）。通过相同机制起作用的另外的化合物包括香草醛（和衍生物）和香草醛（和衍生物）。 GBT 440（Voxelotor，目前处于III期临床试验阶段）。然而，5-HMF，其衍生物， 并且所有通过该机制起作用的防粘化合物都以醛部分为中心， Hb α-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 在大多数情况下经历快速的体内代谢，因此，负责限制血浆半- 许多有前途的候选药物的生命和生物利用度。因此，第一阶段提案的目标是 建立我们的新型最有效的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。这种做法已经证明， 在我们的初步研究中体内药代动力学。预计拟议调查的结果将 帮助获得关键的初步数据，以支持II期更大规模的IND研究。实现SBIR 第一阶段的目标，提出了两个具体目标。具体目标1：3种前药的放大化学合成 衍生物，和对照（即，MSDD 1，未衍生化的天然5-HMF噻唑烷乙酯前药）;和 具体目的2：评价前药在野生型小鼠中的体内PK/PD特性，并且随后，评价前药在野生型小鼠中的体内PK/PD特性。 在SCD的Townes小鼠模型中最有希望的前药候选物。虽然第一阶段提案的目标 是确定一个领先的SCD候选人拥有体内特性和疗效，以支持第二阶段的建议，我们 预期对前体药物衍生化的未开发潜力的更全面理解可能具有 对将来开发用于各种条件的变构Hb调节剂产生深远影响。