NOVEL DRUG FOR URINARY INCONTINENCE

最常见的尿失禁类型是急迫性尿失禁， 治疗不充分，主要是因为目前的药物有不受欢迎的 抗胆碱能副作用，尤其是 老年人。最近有研究表明，膀胱不稳定 这种疾病的基础是钙通道，而不是 胆碱能受体。目前治疗冲动的首选药物 大小便失禁，外消旋奥昔布宁，有两种有效的钙通道 拮抗和抗胆碱能活性，但它有膜 可能导致心脏抑制的稳定作用。具体的 因此，本计划第一阶段的目标是：1.合成一种 一系列专门设计的奥昔布宁衍生物，均为 外消旋体和S对映体；2.获得一种药理活性成分 可预测治疗效果的化合物的概况 促尿失禁，即与地尔硫卓和维拉帕米结合部位 对钙通道的研究；3.获取丹参的药理作用 可预测副作用的化合物，即结合到 M受体与体外心脏抑制活性；4.基于 目标1-3的结果，以合成异构体衍生物 有希望的化合物将具有更长的体内持续时间。 与Bridge Pharma Inc.合作，出现一种或多种化合物 从第一阶段开始，将对其(他们)进行额外的测试 药理和毒理特性，目标是提交 与食品和药物一起研究新药应用 第二阶段结束时的管理。 建议的商业应用 治疗急迫性尿失禁的新药的潜在市场约为 在美国有10亿美元。我们将会使用的化合物 合成具有高效低毒的特点。新出现的毒品 这项工作应该有很好的商业发展潜力。

The most common type of urinary incontinence, Urge Incontinence, is inadequately treated, largely because current drugs have undesirable anticholinergic side effects that are especially problematic among the elderly. It has recently been suggested that the bladder instability underlying this disorder is mediated by calcium channels rather than cholinergic receptors. The current drug of choice for Urge Incontinence, racemic oxybutynin, has both potent calcium channel antagonistic and anticholinergic activities, but it has membrane stabilizing effects that could cause cardiodepression. The specific aims of phase I of this program, therefore are: 1. To synthesize a series of specifically designed derivatives of oxybutynin, both as racemates and as the S-enantiomers; 2. To obtain a pharmacological profile of the compounds that will be predictive of efficacy in treating Urge Incontinence, i.e. binding to diltiazem and verapamil binding sites on calcium channels; 3.To obtain a pharmacological profile of the compounds that will be predictive of side effects, i.e. binding to muscarinic receptors and cardiodepressant activity in vitro; 4.Based on the results of aims 1-3, to synthesize isosteric derivatives of promising compounds that will have prolonged duration of in vivo. In cooperation with Bridge Pharma Inc. one or more compounds emerging from the phase I program will undergo additional testing of its (their) pharmacological and toxicological properties, with the goal of filing and Investigational New Drug application with the Food and Drug Administration at the end of phase II. PROPOSED COMMERCIAL APPLICATION New drugs for Urge Incontinence have a potential market of approximately one billion dollars in the United States. The compounds which we will synthesize have high efficacy and low toxicity. Drugs emerging from this work should have excellent potential for commercial development.