A2a AR Agonists for Rheumatoid Arthritis

A2a AR 激动剂治疗类风湿关节炎

• 批准号: 7108042
• 负责人: JAYSON MICHAEL RIEGER
• 金额: $ 13.76万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108042
• 关键词: adenosine; arthritis; collagen; human; joints; model; rheumatoid arthritis

DESCRIPTION (provided by applicant): This is the first revision of a phase I STTR proposal to develop new therapies for the treatment of rheumatoid arthritis (RA). It is collaboration between a biotechnology company, Adenosine Therapeutics, LLC (ATL) based in Charlottesville, VA, and the University of Virginia laboratory of Dr. Donald L. Kimpel, a Rheumatologist experienced in the study of RA. Human RA is the most common form of inflammatory arthritis and is a chronic disorder of unknown origin with a variable course of disease. The majority of patients with RA have a progressive course which leads to destruction of joint tissue, instability of joints, loss of function and mobility, and increased mortality. Adenosine Therapeutics, LLC has synthesized, patented, and characterized a series of novel, orally available, and selective A2A adenosine receptor (A2AR) agonists that are effective in reducing inflammation in a variety of animal models. Our preliminary data suggest that 1 of these compounds, ATL313, is effective in reducing inflammation and joint damage in a well established rat model of RA. Current drugs used in the management of RA have a variety of side-effects, including cardiovascular complications. Our preliminary dosing and toxicity studies demonstrate no significant side-effects at doses which suppress inflammatory arthritis. Thus, we will further evaluate the effectiveness of the A2AR as a target for RA treatment. The first Aim is to synthesize adequate quantities of ATL313 and its deuterated standard to support these preliminary efficacy and metabolic studies. The second Aim is to characterize the products of the metabolism of these compounds by mouse, rat, dog, and human microsomes and hepatocytes and to confirm the presence of these metabolites in vivo in mice using LC/MS (HPLC coupled Mass Spectroscopy). Our third Aim is to evaluate the efficacy of ATL313 in a collagen-induced model of RA in rats (3A) and mice (3B). We have generated preliminary data that demonstrates the efficacy of ATL313 in a streptococcal cell wall model of arthritis and propose to validate this by comparison to the collagen model. The fourth Aim is to confirm that the A2AR mediates ATL313 activity in the collagen model by co-administering the selective A2AR antagonist ZM241385 (ZM) and to determine the duration of protection afforded by ATL313 by observing animals 60 days after cessation of drug administration.

描述（由申请人提供）：这是I期STTR提案的首次修订，以开发用于治疗类风湿关节炎（RA）的新疗法。这是位于弗吉尼亚州夏洛茨维尔的一家生物技术公司，腺苷Therapeutics，LLC（ATL）与弗吉尼亚大学实验室Donald L. Kimpel博士的合作，这是RA研究中经历的风湿病学家。人类RA是炎症性关节炎的最常见形式，是一种慢性病，其起源不明，疾病病程可变。大多数RA患者都有进行性过程，从而导致关节组织的破坏，关节不稳定，功能丧失和迁移率以及死亡率增加。腺苷疗法有限责任公司已合成，获得专利并表征了一系列新型，口服和选择性的A2A腺苷受体（A2AR）激动剂，可有效减少各种动物模型中的炎症。我们的初步数据表明，其中1种ATL313在RA的大鼠模型中有效减少炎症和关节损伤。 RA管理中使用的当前药物具有多种副作用，包括心血管并发症。我们的初步剂量和毒性研究表明，在抑制炎症性关节炎的剂量下没有明显的副作用。因此，我们将进一步评估A2AR作为RA治疗的靶标的有效性。第一个目的是综合足够数量的ATL313及其犹太标准，以支持这些初步疗效和代谢研究。第二个目的是通过小鼠，大鼠，狗和人的微粒体和肝细胞来表征这些化合物的代谢产物，并使用LC/MS（HPLC偶联质谱）在小鼠中确认这些代谢物在小鼠中的存在。我们的第三个目的是评估ATL313在大鼠（3A）和小鼠（3B）胶原蛋白诱导的RA模型中的功效。我们已经生成了初步数据，该数据证明了ATL313在关节炎的链球菌细胞壁模型中的功效，并建议通过与胶原蛋白模型进行验证。第四个目的是确认A2AR通过共同管理选择性A2AR拮抗剂ZM241385（ZM）来介导ATL313的活性，并确定ATL313提供的保护持续时间，通过观察60天的动物在药物管理后60天通过观察动物。