A Novel Approach to Identify Smooth Muscle Relaxants

识别平滑肌松弛剂的新方法

• 批准号: 6403819
• 负责人: James Joseph Hartman
• 金额: $ 9.99万
• 依托单位: CYTOKINETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2002-03-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6403819
• 关键词: actins; animal tissue; asthma; biotechnology; bronchodilators; chemical structure function; chronic obstructive pulmonary disease; drug discovery /isolation; fluorescent dye /probe; high throughput technology; inhibitor /antagonist; intermolecular interaction; lung; muscle relaxants; muscle relaxation; myosins; protein purification; respiratory disorder; respiratory disorder chemotherapy; respiratory function; respiratory pharmacology; smooth muscle

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) and especially asthma affect millions of Americans. As of 1995, an estimated 14.9 million persons suffer chronic symptoms. Despite several different therapeutic approaches, disease severity also is on the rise as reflected by increasing mortality rates. The treatment of COPD and asthma relies on long-term reduction of the chronic inflammatory response and acute symptomatic control by the use of bronchodilators. In the latter class, inhaled Beta adrenergic agents are most commonly used but suffer from reduced efficacy with prolonged use secondary to receptor desensitization. We propose to begin development of a new class of bronchodilators that act directly on the target responsible for force generation, the motor protein smooth muscle myosin. We plan to introduce this target into Cytokinetic's robust high throughput screening technology to discover compounds that will act via this unique mechanism. Using biochemical and physiological means, these compounds will be screened for secondary undesirable properties and then tested in semi-intact systems. We expect to identify chemical compounds that have the potential to demonstrate proof of principle in relevant models of bronchoconstriction. These compounds may then eventually lead to a novel pharmacologic class of smooth muscle relaxants with applicability in other therapeutic areas. PROPOSED COMMERCIAL APPLICATIONS: Given the number of individuals that use bronchodilators in various lung diseases, the potential market is enormous. The estimated 2002 market size for the most widely used inhaled beta-adrenergic agents (albuterol and salmeterol) is $1.3 billion dollars (Med Ad News, 2000, Vol. 19, p. 59). Agents that directly target the contractile machinery could be used either as adjunctive therapy or potentially as a primary agent. In addition, a potent smooth muscle relaxant may have applications in the other large therapeutic areas such as hypertension, pre-term labor, and bladder spasmaticity leading to incontinence.

描述（由申请人提供）：慢性阻塞性肺疾病 慢性阻塞性肺病（COPD），尤其是哮喘，影响着数百万美国人。截至1995年， 估计有1490万人患有慢性症状。尽管几 不同的治疗方法，疾病的严重程度也在上升， 这反映在死亡率的上升上。治疗COPD和哮喘 依赖于慢性炎症反应和急性炎症反应的长期减少。 使用支气管扩张剂控制症状。在后一类中，吸入 β-肾上腺素能药物是最常用的，但效力降低 长期使用继发于受体脱敏。我们提议开始 开发一类直接作用于靶点的新型支气管扩张剂 运动蛋白平滑肌肌球蛋白负责产生力量。我们 计划将此目标引入Cytokinetic强大的高通量 筛选技术来发现化合物， 机制使用生物化学和生理学手段，这些化合物将被 筛选次要的不良特性，然后在半完整的 系统.我们希望能找出有可能 在支气管收缩的相关模型中证明原理。这些 化合物可能最终导致一种新的药理学类别的光滑 在其它治疗领域具有应用性的肌肉松弛剂。 拟议的商业应用： 考虑到在各种肺部疾病中使用支气管扩张剂的人数，潜在的市场是巨大的。 据估计，2002年最广泛使用的吸入性β-肾上腺素能药物（沙丁胺醇和沙美特罗）的市场规模为13亿美元（Med Ad News，2000年，第19卷，第59页）。直接靶向收缩机制的药物可用作预防性治疗或潜在地用作主要药物。此外，有效的平滑肌松弛剂可应用于其他大的治疗领域，如高血压、早产和导致失禁的膀胱痉挛。