A Novel Approach to Identify Smooth Muscle Relaxants

描述(申请人提供)：慢性阻塞性肺病 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， 据估计，有1490万人患有慢性症状。尽管有几个 不同的治疗方法，疾病的严重程度也在上升 反映在死亡率的上升上。慢性阻塞性肺疾病与哮喘的治疗 依赖于长期减少慢性炎症反应和急性 通过使用支气管扩张剂来控制症状。在后一类中，吸入 β-肾上腺素能药物是最常用的药物，但疗效较差。 长期使用继发于受体脱敏。我们建议开始 一种直接作用于靶点的新型支气管扩张剂的研制 负责力量产生的肌球蛋白是一种肌球蛋白。我们 计划将这一目标引入Cytokinic强大的高吞吐量 筛选技术以发现将通过这种独特的 机制。利用生化和生理手段，这些化合物将被 筛选二次不良特性，然后在半完整状态下进行测试 系统。我们希望识别出那些有可能 在相关的支气管收缩模型中进行原则性证明。这些 化合物最终可能导致一种新的药物类别的平滑 在其他治疗领域具有适用性的肌肉松弛药。 建议的商业应用： 考虑到在各种肺部疾病中使用支气管扩张剂的人数，潜在市场是巨大的。2002年，最广泛使用的吸入型β-肾上腺素能药物(沙丁胺醇和沙美特罗)的估计市场规模为13亿美元(Med Ad News，2000，第19卷，第59页)。直接针对收缩机制的药物既可以用作辅助治疗，也可以作为主要药物使用。此外，一种有效的平滑肌松弛药可能在其他大型治疗领域也有应用，如高血压、早产和导致失禁的膀胱痉挛。

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.