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 Treateutics正在开发第一个治疗性Resolvin分子，旨在管理 类风湿关节炎(RA)。溶血素是内源性的皮摩尔强效小分子，它能激活 复杂的细胞内机制，通过这种机制组织炎症被调节并最终消退。我们的 技术方法得到了研究的支持，研究证明了我们的候选治疗解决方案的有效性 (R-10001)在减少临床相关的类风湿性关节炎啮齿动物模型中的损伤。R-1001潜在地优于其 竞争者凭借：1)一种新的作用机制，有别于现有的治疗方法和 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、钙调神经磷酸酶抑制剂和抗肿瘤坏死因子-α相关的免疫抑制 抑制剂。对大鼠、狗和人类的安全性研究没有发现剂量超过1-2个对数的毒性 有意的治疗性暴露。目的#1：建立肠内R-10001的PK特性，包括关节 关节炎小鼠灌胃给药后的组织分布。我们将全面分析 R-10001的PK配置文件。将测量13C标记的R-10001的血浆和关节组织浓度 在胶原性关节炎雄性SD大鼠给药后。R-10001的完整PK配置文件将 是被建造的。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研究。降低成本并实现大规模 在制造方面，RTX发明了一种新颖的、专有的14步合成路线，作为对 概念以10毫克为标准。即使在这个早期阶段，总体收益率仍为5%，代表着 效率是以前任何合成的5倍以上，成本节约3倍。我们现在希望利用这一点 作为生产克量研究级材料的第一平台的新合成 实例，并将其发展为可行的生产100克和最终千克量的R- 10001。我们现在建议优化我们的新流程，以实现进一步增加3倍于 得率和消除一半的层析分离步骤。这项运动将包括：(I) 识别和改进那些速度和/或产量限制的合成步骤。(Ii) 确定不需要对每种中间体进行离散提纯的伸缩步骤； 审议保护/解除保护战略和保护群体。(Iv)货架期的评估- 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 减少相互竞争的副作用。(6)用于扩大规模的试剂的选择--如有可能，用SAFE取代； 常规的、更便宜的试剂；(Vii)检查色谱分离的替代品；(Viii) 开发分析中间体和相关杂质的分析方法；(Ix)产生 多个10克批次；和(X)开发批量分析和释放原料药的分析方法。