A2a AR Agonists for Rheumatoid Arthritis

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性关节炎（RA）的新疗法。它是一家生物技术公司，位于弗吉尼亚州夏洛茨维尔的Adenosine Therapeutics， LLC （ATL）和弗吉尼亚大学的Donald L. Kimpel博士的实验室合作的，Donald L. Kimpel博士是一位在类风湿关节炎研究方面经验丰富的风湿病学家。人类类风湿性关节炎是炎症性关节炎最常见的形式，是一种病因不明的慢性疾病，病程多变。大多数RA患者有一个渐进的过程，导致关节组织破坏，关节不稳定，功能和活动能力丧失，死亡率增加。Adenosine Therapeutics， LLC合成了一系列新颖的、可口服的、选择性的A2A腺苷受体（A2AR）激动剂，并获得了专利，这些激动剂在各种动物模型中都能有效减少炎症。我们的初步数据表明，这些化合物中的一种，ATL313，在一个建立良好的RA大鼠模型中有效地减少炎症和关节损伤。目前用于治疗类风湿性关节炎的药物有各种各样的副作用，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及其氘化标准物，以支持这些初步的疗效和代谢研究。第二个目的是表征这些化合物在小鼠、大鼠、狗和人类微粒体和肝细胞中的代谢产物，并使用LC/MS （HPLC耦合质谱）确认这些代谢物在小鼠体内的存在。我们的第三个目标是评估ATL313在大鼠（3A）和小鼠（3B）胶原诱导的RA模型中的疗效。我们已经生成了初步数据，证明了ATL313在关节炎链球菌细胞壁模型中的有效性，并建议通过与胶原模型的比较来验证这一点。第四个目的是通过联合使用选择性A2AR拮抗剂ZM241385 （ZM）来证实A2AR在胶原模型中介导ATL313的活性，并通过停药后60天观察动物来确定ATL313的保护持续时间。

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.