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正在开发第一个用于管理 类风湿关节炎（RA）。 resolvins是激活A的内源性皮摩尔功能小分子 通过调节组织注射并最终解决组织的复杂细胞内机制。我们的 通过研究证明我们候选治疗的实用性的研究支持了技术方法 （R-10001）减少与RA的临床啮齿动物模型的损伤。 R-1001可能优于其 竞争对手以：1）一种新颖的作用机理，与现有疗法和中的那些不同 开发，以及2）增加宿主免疫防御的能力，而不是更典型的 与甲氨蝶呤，钙调蛋白抑制剂和抗TNF-α有关的免疫抑制 抑制剂。在大鼠，狗和人类中的安全研究并未显示出剂量1-2的毒性。 预期的治疗暴露。 AIM＃1：建立肠内R-10001的PK属性，包括关节 伸向关节炎的小鼠后，组织分布。我们将对 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 在用胶原蛋白诱导的关节炎的雄性SD大鼠给药。 R-10001的完整PK配置文件将 被构造。 AIM＃2：扩展R-10001的合成路线，并生成足够的批次 主要参考标准和药理学研究。降低成本并允许大规模 制造业RTX发明了一条新颖的，专有的14步合成路线，作为证明 概念以10毫克的比例。即使在这个早期阶段，总产量也为5％，代表 效率超过5倍的任何事先合成和3倍成本节省的效率。我们现在希望利用这个 新合成是第一届研究级材料的平台 实例并将其发展为可行的制造过程，持续100 g，并最终kg数量的R- 10001。我们现在建议以进一步增加3倍的意图来优化我们的新过程 产量和消除一半色谱隔离步骤。该活动将包括：（i） 识别和改进率和/或限制率的合成步骤。 （ii） 识别不需要每个中间体纯化的电信步骤； （iii） 考虑保护/弃用策略和保护群体。 （iv）评估保质期 - 在适当的窗口内使用不稳定的中间体； （v）分析副产品以理解和 减少竞争副反应。 （vi）选择用于扩大缩放的试剂 - 在可能的情况下替换 常规，更便宜的试剂； （vii）检查色谱分离的替代方案； （viii） 开发用于分析中间体和相关杂质的分析方法； （ix）产生 多10 g批次； （x）开发用于批处理分析和释放API的分析方法。