Antagonists of A2B Adenosine Receptors for Asthma

描述(由申请人提供)：这是一项第二阶段的SBIR提案，旨在开发一种治疗哮喘的新疗法。预期的结果将是确定一种替代茶碱的治疗候选药物，茶碱是一种非选择性腺苷受体拮抗剂，对治疗哮喘有效，但受到副作用的限制，主要是失眠，通过阻断大脑中的A1AR介导。这项提议延续了位于弗吉尼亚州夏洛茨维尔的一家生物技术公司--腺苷治疗有限责任公司(ATL)与弗吉尼亚大学乔尔·林登实验室之间的合作。乔尔·林登博士是研究腺苷受体的专家。现已完成的第一阶段SBIR方案是基于A2B腺苷受体(A2BAR)拮抗剂抑制变应原介导的肥大细胞激活的假设。这是基于观察到选择性A2B阻滞剂，如我们的专利化合物MRS1754，抑制腺苷介导的某些肥大细胞系的激活，如犬BR和人HMC-1肥大样细胞。在第一阶段，我们优化了制备纯化的人肺肥大细胞的程序，我们证明这些细胞具有促进变应原介导的脱颗粒的功能A2BARs。MRS174不是治疗的候选药物，因为它的水溶性很低，生物利用度很差。由该提案的首席研究员罗伯特·汤普森博士领导的腺苷治疗公司的化学家们现在已经成功地合成了一种新的专有选择性A2BAR阻滞剂家族，这些阻滞剂是生物可用的，也是治疗的候选药物。其中一种新化合物(ATL829)已经在过敏性绵羊身上进行了测试，并被证明可以减少50%腺苷介导的支气管痉挛。这一第二阶段SBIR应用的主要目标是确定一种用于治疗哮喘的A2BR拮抗剂候选药物，该药物在绵羊哮喘模型中口服可用、有效和有效。我们建议开发大规模合成临床候选化合物的程序(目标1)，筛选对人肥大细胞具有活性的A2BAR治疗候选化合物(目标2)，并评估测试化合物在绵羊身上的口服活性(目标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)。绵羊研究将由佛罗里达州迈阿密海滩的西奈山医疗中心的威廉·亚伯拉罕博士根据合同进行。这些目标与国家过敏和传染病研究所的使命直接相关，该研究所的使命是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病、免疫学和过敏性疾病，目标是针对哮喘的药物开发，目前的治疗方法对患者护理并不理想。该项目的目标是开发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。在绵羊身上令人振奋的新的初步数据证实了一类新的专有A2B腺苷受体拮抗剂的有效性。目前的治疗方法受到疗效有限、快速反应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.