NOVEL DRUGS TO TREAT URINARY INCONTINENCE

这项研究的目的是开发治疗尿失禁的新药，尿失禁是越来越多的人，特别是老年人的一种痛苦。有必要改进最常见类型的治疗，即急迫性尿失禁，因为目前的药物具有不良的抗胆碱能和致心律失常副作用。在第一阶段，我们确定了一种可供进一步开发的先导化合物。第二阶段的研究计划包括：(1)继续评价先导化合物的药理性质，即奥昔布宁的(S)-双羟乙基酰胺类似物(DIHED)。方法将包括：使用豚鼠膀胱条的体外抗痉挛活性和在体内模型中的活性，如第4节所述。合成具有羟基烷基氨基取代的附加衍生物，并预期作用时间更长。这些化合物将具有酮甲基或a，a-二甲基酯基团来代替不稳定的氧丁宁酯。(3)。继续测试所有新化合物，包括与钙通道和毒鼠碱受体结合的研究，使用豚鼠膀胱条进行的体外活性研究，以及第4节所述的体内模型活性的研究。优化合成和手性拆分方法以及放大生产，以提供研究所需的候选药物的数量。GMP合成的商业实验室最终将被确定为主要的临床候选药物。(3)。与Bridge Pharma Inc.合作，并可能与默克公司、McNeil Consumer Healthcare或另一家“大制药公司”合作，通过临床前研究来支持向FDA提出的研究新药(IND)申请，从而确定一个或多个主要候选药物。与健康相关。对改善急迫性尿失禁药物的需求非常强烈。这项工作将导致开发治疗这种疾病的新药，而不会产生副作用，而且既具有技术创新，又与人类健康高度相关。拟议的商业应用：治疗尿失禁的新药在美国的潜在市场约为10亿美元。我们将要合成和开发的化合物将具有高效、低毒的特点。从这项工作中产生的药物应该具有很好的商业开发潜力。

The objective of this research is to develop new drugs to treat urinary incontinence, an affliction of a growing segment of the population, especially the elderly. There is a need for improved treatment of the most common type, Urge Incontinence, because current drugs have undesirable anticholinergic and arrythmogenic side effects. In phase I we identified a lead compound for further development. The research plan for phase II combines: (1) continued evaluation of the pharmacological properties of the lead compound, the (S)-bis-hydroxyethyl amide analog of oxybutynin (DIHED). Approaches will include: in vitro antispasmodic activity using guinea pig bladder strips and activity in in vivo models as described in section 4. (2). synthesis of additional derivatives with hydroxyalkylamino substitutions and expected longer duration of action. These compounds will have a ketomethyl group or a,a-dimethyl ester group in place of the labile ester of oxybutynin. (3). continued testing of all new compounds, including studies of binding to calcium channels and muscarinic receptors, in vitro activity using guinea pig bladder strips, and activity in in vivo models as described in section 4. (4). optimization of synthetic and chiral resolution methods and scale-up production to afford the quantities of drug candidates needed for the studies. Commercial laboratories for GMP syntheses will ultimately be identified for the lead clinical candidate. (3). identification of one or more lead drug candidates to carry forward, in collaboration with Bridge Pharma Inc. and possibly with Merck and Co., McNeil Consumer Healthcare or another "big pharma", with preclinical studies to support an Investigational New Drug (IND) application to the FDA. Health relatedness. The demand for improved medication of Urge Incontinence is very strong. This work will result in the development of new drugs to treat the disease with no side effects, and is both technologically innovative and highly relevant to human health. PROPOSED COMMERCIAL APPLICATIONS: New drugs for Urge Incontinence have a potential market of approximately one billion dollars in the United States. The compounds which we will synthesize and develop will have high efficacy and low toxicity. Drugs emerging from this work should have excellent potential for commercial development.