Antagonists of A2B Adenosine Receptors for Asthma

A2B 腺苷受体拮抗剂治疗哮喘

• 批准号: 7155367
• 负责人: ROBERT D THOMPSON
• 金额: $ 75.55万
• 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: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155367
• 关键词: adenosine; allergens; asthma; human; lead; lung; mast cell; model; purinergic receptor; receptor; sheep

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.

描述（由申请人提供）：这是一项II期SBIR提案，用于开发一种用于治疗哮喘的新疗法。预期的结果将是鉴定治疗性候选者来替代茶碱，这是一种非选择性腺苷受体拮抗剂，可有效治疗哮喘，但受副作用的限制，主要是失眠症，主要是由封锁大脑中的A1AR介导的。该提案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Therapeutics，LLC（ATL）与乔尔·林登（Joel Linden）博士学位的弗吉尼亚大学实验室，腺苷受体研究专家。现在完成的I期SBIR提案是基于以下假设：A2b腺苷受体（A2BAR）抑制过敏原介导的肥大细胞激活的拮抗剂。这是基于这样的观察结果，即我们的专有化合物MRS1754等选择性A2B阻滞剂抑制腺苷介导的某些肥大细胞系的激活，例如犬BR和人类HMC-1桅杆样细胞。在第一阶段，我们优化了制备纯化的人肺肥大细胞的程序，我们表明这些细胞具有促进过敏原介导的脱粒的功能性A2BAR。 MRS174不是治疗候选者，因为它的水溶性非常低，生物利用度差。该提案首席研究员罗伯特·汤普森（Robert Thompson，Ph.D.）领导的腺苷治疗学的化学家现在已经成功地综合了一个新的专有选择性的A2BAR阻滞剂，这些家族是生物可利用和治疗候选者的。其中一种新化合物（ATL829）已在过敏绵羊中进行了测试，并显示出降低> 50％的腺苷介导的支气管痉挛。该II期SBIR应用的主要目标是确定用于治疗哮喘的A2BR拮抗剂治疗候选者，该疗法在绵羊哮喘模型中口服，有效和有效。我们建议开发用于大规模合成临床候选物的程序（AIM 1），筛选A2BAR治疗候选者，用于人类肥大细胞的活性（AIM 2），并评估绵羊中测试化合物的口腔活性（AIM 3）。我们将评估绵羊哮喘模型中的三个候选药物，以识别最佳的铅治疗候选和一种备用化合物（AIM 4）。绵羊研究将由佛罗里达州迈阿密海滩的西奈山医学中心的威廉·亚伯拉罕博士在合同的基础上进行。这些目标直接与国家过敏和传染病研究所的使命有关，该疾病的使命是通过针对哮喘的药物发育进行旨在更好地理解，治疗和最终预防传染性，免疫和过敏性疾病的基础和应用研究，以便当前的疗法对患者护理不是理想的疗法。该项目的目的是开发改进的药物来治疗哮喘，这种疾病会影响数百万美国人。令人兴奋的绵羊新初步数据确立了新专有类A2B腺苷受体拮抗剂的有效性。当前的疗法受到有限的疗效，速度或不良副作用的困扰。