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 提案的第一次修订，旨在开发治疗类风湿关节炎 (RA) 的新疗法。该项目是位于弗吉尼亚州夏洛茨维尔的生物技术公司 Adenosine Therapeutics, LLC (ATL) 与弗吉尼亚大学 Donald L. Kimpel 博士（一位在 RA 研究方面经验丰富的风湿病学家）实验室之间的合作。人类 RA 是最常见的炎症性关节炎，是一种病因不明、病程可变的慢性疾病。大多数 RA 患者病程呈进行性发展，导致关节组织破坏、关节不稳定、功能和活动能力丧失以及死亡率增加。 Adenosine Therapeutics, LLC 合成了一系列新型口服选择性 A2A 腺苷受体 (A2AR) 激动剂，并获得专利并对其进行了表征，这些激动剂可有效减少各种动物模型的炎症。我们的初步数据表明，其中一种化合物 ATL313 可有效减少已建立的 RA 大鼠模型中的炎症和关节损伤。目前用于治疗 RA 的药物有多种副作用，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 治疗靶点的有效性。第一个目标是合成足够数量的 ATL313 及其氘代标准品，以支持这些初步功效和代谢研究。第二个目标是表征小鼠、大鼠、狗和人类微粒体和肝细胞代谢这些化合物的产物，并使用 LC/MS（HPLC 耦合质谱）确认小鼠体内这些代谢物的存在。我们的第三个目标是评估 ATL313 在胶原诱导的大鼠 (3A) 和小鼠 (3B) RA 模型中的功效。我们已经生成了初步数据，证明 ATL313 在关节炎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比较来验证这一点。第四个目标是通过共同施用选择性 A2AR 拮抗剂 ZM241385 (ZM) 来确认 A2AR 在胶原蛋白模型中介导 ATL313 活性，并通过在停止给药后 60 天观察动物来确定 ATL313 提供的保护持续时间。