A pro-resolution lipid mediator for treatment of rheumatoid arthritis

用于治疗类风湿性关节炎的促消退脂质介质

• 批准号: 9341073
• 负责人: PRAKASH G JAGTAP
• 金额: $ 75万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341073
• 关键词: Acute Lung Injury; Arthritis; Attention; Binding; Blood; Calcineurin inhibitor; Canis familiaris; Chondrocytes; Clinical; Clinical Research; Clinical Trials; Colitis; Collagen-Induced Arthritis; Complex; Cost Savings; Data; Development; Disease; Dose; Drug or chemical Tissue Distribution; Enteral; Excision; Experimental Models; Fibrosis; Future; G-Protein-Coupled Receptors; Generations; Goals; Human; Immune; Immunosuppression; Inflammation; Inflammatory; Injury; Isomerism; Joints; Kidney; Label; Lead; Legal patent; Life; Lipid Chemistry; Measures; Mediator of activation protein; Medical; Methods; Methotrexate; Mus; Myeloid Cells; Oral; Periodontitis; Peritonitis; Pharmacologic Substance; Pharmacology Study; Phase; Plasma; Pneumonia; Pre-Clinical Model; Process; Production; Property; Publications; Rattus; Reaction; Reagent; Reference Standards; Refractory; Research; Research Institute; Research Support; Resolution; Rheumatoid Arthritis; Rodent Model; Route; Safety; Series; Side; Signal Transduction; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Translating; Validation; analytical method; autoimmune arthritis; base; cell injury; chemokine; clinically relevant; cost; cytokine; improved; in vivo; insight; invention; lipid mediator; male; manufacturing process; neutrophil; novel; safety study; scale up; small molecule; therapeutic candidate; tumor necrosis factor-alpha inhibitor

Radikal Therapeutics is developing the first therapeutic Resolvin molecule intended for the management of rheumatoid arthritis (RA). Resolvins are endogenous picomolar-potent small molecules that activate a complex intracellular mechanism by which tissue inflammation is modulated and ultimately resolved. Our technical approach is supported by research demonstrating the utility of our candidate therapeutic Resolvin (R-10001) in reducing injury in clinically-relevant rodent models of RA. R-1001 is potentially superior to its competitors by virtue of: 1) a novel mechanism of action, distinct from existing therapies and those in development, and 2) its ability to increase host immune defense, as opposed to the more typical immunosuppression that is associated with methotrexate, calcineurin inhibitors, and anti-TNF-α inhibitors. Safety studies in rats, dogs, and humans do not reveal toxicity at doses 1-2 logs in excess of the intended therapeutic exposure. Aim #1: Establish the PK properties of enteral R-10001, including joint tissue distribution following gavage delivery to mice with arthritis. We will undertake a full analysis of the PK profile of R-10001. Plasma and joint tissue concentrations of 13C-labeled R-10001 will be measured following administration to male SD rats with collagen-induced arthritis. A full PK profile of R-10001 will be constructed. Aim #2: Scale up the synthetic route of R-10001 and generate batches sufficient for primary reference standard and pharmacology studies. To lower cost and allow for large-scale manufacturing, RTX has invented a novel, proprietary, 14-step synthetic route performed as a proof-of- concept at a 10 mg scale. Even at this early stage, the overall yield is 5% and represents an improvement in efficiency of over 5-times that of any prior synthesis and a 3-fold cost saving. We now wish to utilize this new synthesis as a platform for the production of gram amounts of research grade material in the first instance and to develop this into a viable manufacturing process for 100 g and ultimately kg amounts of R- 10001. We now propose to optimize our new process with the intent of achieving a further 3-fold increase in yield and elimination of half of the chromatographic isolation steps. The campaign will include: (i) identification and improvement of those synthetic steps that are rate and/or yield limiting. (ii) identification of those telescoping steps that do not require discrete purification of each intermediate; (iii) consideration of protection/deprotection strategies and protecting groups. (iv) assessment of the shelf-life - use of unstable intermediates within an appropriate window; (v) analysis of by-products to understand and reduce competing side-reactions. (vi) choice of reagents for scale-up – replace, where possible, with safe, routine, cheaper reagents; (vii) examination of alternatives to chromatographic separations; (viii) development of analytical methods for analysis of intermediates and relevant impurities; (ix) generation of multi-10 g batches; and (x) development of analytical methods for batch analysis and release of the API.

Radikal Therapeutics 正在开发第一个治疗性 Resolvin 分子，旨在用于治疗 类风湿性关节炎（RA）。 Resolvins 是内源性皮摩尔级小分子，可激活 复杂的细胞内机制，通过该机制调节并最终解决组织炎症。我们的 技术方法得到了研究的支持，证明了我们的候选治疗药物 Resolvin 的实用性 (R-10001) 可减少临床相关的 RA 啮齿动物模型的损伤。 R-1001 可能优于其 竞争对手凭借：1）一种新颖的作用机制，不同于现有的疗法和现有的疗法 发育，以及 2) 其增强宿主免疫防御的能力，而不是更典型的 与甲氨蝶呤、钙调磷酸酶抑制剂和抗 TNF-α 相关的免疫抑制 抑制剂。在大鼠、狗和人类中进行的安全性研究并未显示出超过剂量 1-2 个对数级的毒性。 预期的治疗性暴露。目标#1：建立肠内 R-10001 的 PK 特性，包括联合作用 强饲给患有关节炎的小鼠后的组织分布。我们将对此进行全面分析 R-10001 的 PK 概况。将测量 13C 标记的 R-10001 的血浆和关节组织浓度 给患有胶原诱导关节炎的雄性 SD 大鼠给药后。 R-10001 的完整 PK 概况将 被建造。目标#2：扩大 R-10001 的合成路线并产生足够的批次 主要参考标准和药理学研究。为了降低成本并允许大规模 在制造过程中，RTX 发明了一种新颖的、专有的、14 步合成路线，作为证明- 10 毫克规模的概念。即使在这个早期阶段，总体收益率也达到了 5%，这表明了 效率是之前任何合成方法的 5 倍以上，并且成本节省了 3 倍。我们现在希望利用这个 新合成作为首次生产克量研究级材料的平台 例如，并将其开发为可行的生产工艺，可生产 100 克并最终达到公斤量的 R- 10001.我们现在建议优化我们的新流程，旨在实现进一步增加 3 倍 产率并消除了一半的色谱分离步骤。该活动将包括：(i) 识别和改进那些限制速率​​和/或产量的合成步骤。 (二) 确定不需要对每个中间体进行单独纯化的那些伸缩步骤； (三) 考虑保护/去保护策略和保护群体。 (iv) 保质期评估 - 在适当的窗口内使用不稳定的中间体； (v) 分析副产品以了解和 减少竞争性副反应。 (vi) 选择用于放大的试剂——在可能的情况下，用安全的、 常规、便宜的试剂； (vii) 检查色谱分离的替代方案； （八） 开发用于分析中间体和相关杂质的分析方法； (九) 产生 多10克批次； (x) 开发用于批量分析和 API 发布的分析方法。