Novel Drugs to Treat Urinary Incontinence

描述(由申请人提供)：在美国，相当大比例的成年人患有膀胱过度活动(OAB)，这个问题在老年人中更为严重。除了尿布的使用，目前市场上占主导地位的两种药物是托特罗定和奥昔布宁，但它们的治疗效果是由于它们强大的抗霉菌活性。这些药物仅适用于对阿托品敏感的患者群体，而且疗效不大，因为治疗剂量受到严重的抗肉毒杆菌副作用的限制，如口干、视力模糊和记忆障碍，这些副作用在老年人中尤其严重。我们通过这项第二阶段SBIR赠款发现的“欧洲选择性”钙拮抗剂，例如“TBDT”，即去异丙基托特罗定的5-叔丁基类似物，无论收缩的原因是什么，都能抑制不必要的膀胱平滑肌收缩。因此，我们预计TBDT将对所有患有OAB的患者具有治疗价值--无论他们是阿托品耐药还是阿托品敏感。与硝苯地平和地尔硫卓等其他钙拮抗剂相反，TBDT抑制膀胱收缩，但不影响心脏功能和血压。与目前的治疗方法相比，TBDT预计不会有任何抗霉菌副作用。对于这一竞争性的续期应用，我们建议改进TBDT的合成工艺和分析方法，并进行安全药理学、毒理学和毒代动力学研究，使我们能够获得监管机构(FDA)的批准，进行TBDT的人体临床试验。我们选择了5-丙基衍生物PrBDT作为备用化合物。该项目的具体目标是：1.开发合成方法来制造TBDT，并制备用于稳定性和口服生物利用度比较的盐形式；2.使用TBDT及其中间体的分析方法来支持合成方法的开发，并将用于TBDT分析的方法转移到以后的毒代动力学研究中；3.利用人体微粒体和肝细胞进行TBDT的体外代谢研究，以及用于毒理学的相关动物体内的代谢研究；4.使用本申请中描述的方法学进行安全性药理学研究；5.进行监管批准IND所需的毒理学研究；6.为TBDT编写IND申请，并与FDA召开IND前会议。最终目标是将该项目授权给一家在药物开发和监管批准方面有经验的公司，并有能力在美国和世界各地将该药物商业化。我们的合作伙伴Bridge Pharma Inc.以前在授权研究项目方面拥有经验。本工作的成功完成将产生批准该药物或启动人体临床试验所需的数据。以一种新的机制作用于OAB的药物不仅在商业上具有竞争力，而且将提高老年人的依从性和生活质量。老年人膀胱过度活动症(OAB)的发生率不断增加，给这种疾病的治疗带来了巨大的挑战。如今的替代品是尿布或药物，如特罗地林和奥昔布宁，它们有显著的抗胆碱能副作用，特别是在老年患者中。GL合成和Bridge Pharma正在开发的新药物类别是欧洲选择性钙拮抗剂，承诺具有高治疗效益，而不会出现现有药物的典型副作用。这种新药将极大地提高OAB患者的生活质量。

DESCRIPTION (provided by applicant): A significant percentage of adults in the US suffer from overactive bladder (OAB), and the problem is more acute in the elderly. Aside from the use of diapers, two drugs currently dominate the market, tolterodine and oxybutynin, but their therapeutic effects are due to their potent antimuscarinic activities. These drugs address only the "atropine-sensitive" patient population, and are marginally effective because therapeutic doses are limited by severe antimuscarinic side effects, such as dry mouth, blurred vision and memory impairment which are particularly problematic in the elderly. The "uro-selective" calcium antagonists that we have discovered through this phase II SBIR grant, exemplified by "TBDT", the 5-t-butyl analog of des-isopropyl tolterodine, inhibit unwanted smooth muscle contractions of the bladder regardless of the reason for the contractions. We, therefore, expect that TBDT will have therapeutic value for all patients suffering from OAB - regardless if they are atropine-resistant or atropine-sensitive. Contrary to other calcium antagonists such as nifedipine and diltiazem, TBDT inhibits bladder contraction but affects neither heart functions nor blood pressure. In contrast with the current therapy, TBDT is not expected to have any antimuscarinic side effects. For this competing renewal application, we propose to improve the synthetic process and analytical methods for TBDT, and carry out the safety pharmacology, toxicology and toxicokinetic studies that will enable us to obtain regulatory (FDA) approval to conduct human clinical trials of TBDT. We have selected the 5-propyl derivative PrBDT as a backup compound. The specific aims for this project are : 1. To develop synthetic methods to manufacture TBDT, and to prepare salt forms for comparison of stability and oral bioavailability; 2. To use analytical methods for TBDT and its intermediates to support synthesis methods development, and to transfer methods for TBDT analysis for later toxicokinetic studies; 3. To perform metabolism studies of TBDT in vitro, using human microsomes and hepatocytes, and in vivo, in relevant animal species to be used for toxicology; 4. To perform safety pharmacological studies, using methodology described in this application; 5. To perform toxicological studies necessary for regulatory approval of an IND; 6. To write the IND application for TBDT and to conduct a pre-IND meeting with the FDA. The ultimate aims are to license this project to a company with experience in drug development and regulatory approval, and the ability to commercialize the drug in the United States and worldwide. Our partner Bridge Pharma Inc. has previous experience in outlicensing research projects. Successful conclusion of the present work will generate the data necessary to license the drug or to initiate human clinical trials. A drug for OAB acting by a novel mechanism will not only be competitive commercially, but will improve compliance and quality of life of the elderly. Increasing incidence of overactive bladder (OAB) in the elderly creates a major challenge for treatment of this affliction. The alternatives today are diapers or drugs, such as terodiline and oxybutynin, which have significant anticholinergic side effects especially in older patients. The new drug class under development by GLSynthesis and Bridge Pharma, uro-selective calcium antagonists, promise to have high therapeutic benefit without the typical side effects of the current drugs. The new drug will greatly increase the quality of life of persons with OAB.