Antagonists of A2B Adenosine Receptors for Asthma

描述（由申请方提供）：这是一项II期SBIR提案，旨在开发一种治疗哮喘的新疗法。期望的结果将是鉴定替代茶碱的治疗候选物，茶碱是一种非选择性腺苷受体拮抗剂，其在治疗哮喘中是有效的，但受到副作用的限制，主要是失眠，通过阻断脑中的A1 AR介导。该提案继续了位于弗吉尼亚州夏洛茨维尔的生物技术公司Adenosine Therapeutics，LLC（ATL）与腺苷受体研究专家Joel林登博士的弗吉尼亚大学实验室之间的合作。现在完成的I期SBIR提案是基于A2 B腺苷受体（A2 BAR）拮抗剂抑制过敏原介导的肥大细胞活化的假设。这是基于以下观察结果：选择性A2 B阻断剂（如我们的专利化合物MRS 1754）抑制腺苷介导的某些肥大细胞系（如犬BR和人HMC-1肥大样细胞）的活化。在第一阶段，我们优化了制备纯化的人肺肥大细胞的程序，我们发现这些细胞具有功能性A2 BAR，有助于过敏原介导的脱粒。MRS 174不是治疗候选物，因为它具有非常低的水溶性和差的生物利用度。腺苷治疗公司的化学家，由该提案的主要研究者罗伯特·汤普森博士领导，现在已经成功地合成了一个新的家族的专有选择性A2 BAR阻滞剂，是生物可利用的和治疗的候选者。其中一种新化合物（ATL 829）已在过敏性绵羊中进行了测试，并显示可减少> 50%的腺苷介导的支气管痉挛。该II期SBIR申请的主要目标是确定用于治疗哮喘的A2 BR拮抗剂治疗候选药物，该药物在绵羊哮喘模型中可口服、强效且有效。我们建议开发用于临床候选物的大规模合成的程序（目的1），筛选A2 BAR治疗候选物对人肥大细胞的活性（目的2），并评估测试化合物在绵羊中的口服活性（目的3）。我们将在绵羊哮喘模型中评估三种候选药物，以确定最佳的先导治疗候选药物和一种备用化合物（目标4）。绵羊研究将由William Abraham博士在佛罗里达迈阿密海滩的西奈山医学中心根据合同进行。这些目标直接关系到国家过敏和传染病研究所的使命，即通过针对哮喘的药物开发，进行和支持基础和应用研究，以更好地了解，治疗和最终预防传染性，免疫性和过敏性疾病，目前的治疗方法对于患者护理并不理想。该项目的目标是开发用于治疗哮喘的改进药物，哮喘是一种影响数百万美国人的疾病。令人兴奋的新的初步数据在羊建立了一个新的专利类A2 B腺苷受体拮抗剂的有效性。目前的治疗方法受到疗效有限、快速耐受或不良副作用的困扰。

DESCRIPTION (provided by applicant): This is a Phase II SBIR proposal to develop a new therapy for the treatment of asthma. The desired outcome will be the identification of a therapeutic candidate to replace theophylline, a non-selective adenosine receptor antagonist that is effective in treating asthma, but limited by side effects, primarily insomnia, mediated by blockade the A1AR in the brain. This proposal continues the collaboration between a biotechnology company, Adenosine Therapeutics, LLC (ATL) located in Charlottesville, VA and the University of Virginia laboratory of Joel Linden, PhD, an expert in the study of adenosine receptors. The now completed Phase I SBIR proposal was predicated on the hypothesis that antagonists of the A2B adenosine receptor (A2BAR) inhibit allergen-mediated activation of mast cells. This was based on the observation that selective A2B blockers such as our proprietary compound, MRS1754, inhibit adenosine-mediated activation of certain mast cell lines such as canine BR and human HMC-1 mast-like cells. In Phase I we optimized procedures for preparing purified human lung mast cells and we showed that these cells have functional A2BARs that facilitate allergen-mediated degranulation. MRS174 is not a therapeutic candidate since it has very low aqueous solubility and poor bioavailability. Chemists at Adenosine Therapeutics, headed by the Principal Investigator of the proposal, Robert Thompson, Ph.D., have now succeeded in synthesizing a new family of proprietary selective A2BAR blockers that are bioavailable and therapeutic candidates. One of the new compounds (ATL829) has been tested in allergic sheep and shown to reduce by > 50% adenosine mediated bronchospasm. The primary goal of this Phase II SBIR application is to identify an A2BR antagonist therapeutic candidate for the treatment of asthma that is orally available, potent, and efficacious in a sheep asthma model. We propose to develop procedure for the large scale synthesis of clinical candidates (Aim 1), screen A2BAR therapeutic candidates for activity on human mast cells (Aim 2) and evaluate oral activity of the test compounds in sheep (Aim 3). We will evaluate three drug candidates in sheep asthma models to identify an optimal lead therapeutic candidate and one backup compound (Aim 4). Sheep studies will be done on a contractual basis by Dr. William Abraham at Mount Sinai Medical Center in Miami Beach, Florida. These objectives directly relate to the mission of the National Institute of Allergy and Infectious Diseases, which is to conduct and support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases, by targeting drug development for asthma, for which current therapies are not ideal for patient care. The goal of this project is to develop improved drugs for the treatment of Asthma, a disease that affects millions of Americans. Exciting new preliminary data in sheep establishes the effectiveness of a new proprietary class of A2B adenosine receptor antagonists. Current therapies are plagued by limited efficacy, tachyphylaxis, or adverse side effects.