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正在开发第一种治疗性Resolvin分子，用于治疗 类风湿性关节炎（RA）。消退素是一种内源性皮摩尔强效小分子，可激活 组织炎症通过复杂的细胞内机制调节并最终消退。我们 一种技术方法得到了研究的支持，该研究证明了我们的候选治疗药物Resolvin的效用 （R-10001）在临床相关的RA啮齿动物模型中减少损伤。R-1001可能优于其上级 竞争对手凭借：1）一种新的作用机制，不同于现有的疗法和那些在 发展，和2）它的能力，以增加宿主的免疫防御，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 抑制剂的在大鼠、犬和人中的安全性研究未显示超过1-2 log的剂量的毒性。 预期治疗暴露。目的1：确定肠内R-10001的PK特性，包括联合给药 灌胃给药后的组织分布。我们将全面分析 R-10001的PK特征。将测量13 C标记R-10001的血浆和关节组织浓度 对患有胶原诱导性关节炎的雄性SD大鼠给药后。R-10001的完整PK特征将 被建造。目的#2：扩大R-10001的合成路线，并生成足以用于以下目的的批次 一级参比标准品和药理学研究。为了降低成本， RTX发明了一种新颖的，专有的，14步合成路线， 10毫克规模的概念。即使在这个早期阶段，总收率也为5%，并且代表了在以下方面的改进： 效率是任何现有合成的5倍以上，成本节省3倍。我们现在希望利用这个 新的合成作为一个平台，生产克量的研究级材料，在第一个 实例，并将其开发成用于100 g和最终kg量的R- 10001.我们现在建议优化我们的新工艺，以实现进一步增加3倍， 产率和消除一半的色谱分离步骤。该运动将包括： 鉴定和改进那些限制速率和/或产率的合成步骤。（二） 鉴定不需要对每种中间体进行离散纯化的那些套叠步骤;（iii） 考虑保护/去保护策略和保护基团。(iv)保质期评估- 在适当的时间范围内使用不稳定的中间体;（v）分析副产品， 减少竞争性副反应。(vi)选择用于扩大规模的试剂-在可能的情况下， 常规、较便宜的试剂;（七）审查色谱分离的替代办法;（八） 开发用于分析中间体和相关杂质的分析方法;（ix）生成 多个10 g批次;和（x）开发批分析和放行API的分析方法。