Targeting the relief of chronic pain with orally active peroxynitrite decompositi

描述(申请人提供)：三分之一的美国人患有某种形式的慢性疼痛(30%对止痛治疗有抵抗力)，这使其成为一个严重的健康问题，具有严重的经济影响(估计每年的成本约为1000亿美元)。与复杂的区域疼痛综合征相关的慢性疼痛尤其难以管理。与炎症性疾病相关的慢性疼痛，如类风湿性关节炎，在临床上往往很难治疗，因为对涉及的伤害性通路了解不足。目前的药物治疗方案效果不佳，而且往往表现出不可接受的副作用。在过去的十年里，我们的多学科团队已经产生了实验结果，这些结果清楚地表明，除了吗啡诱导的痛敏和抗伤害耐受性的发展外，过氧亚硝酸盐作为炎症和慢性疼痛状态的关键介质的过度产生也是可能的。因此，以类似酶的催化方式作用的小分子药物直接清除这种神经毒性物质为一种全新的止痛策略提供了一种非传统的方法。压倒一切的目标是广泛有效地治疗与炎症性疾病相关的慢性疼痛。因此，将合成一系列具有膜穿透性能的金属电荷屏蔽型金属卟啉和卟啉类化合物，并筛选其作为过氧亚硝酸根分解催化剂。随后将进行药代动力学和生物利用度研究。表现出最高催化活性的化学实体具有类似药物的特性，然后将在两个成熟的炎症和关节炎动物模型中测试止痛效果和效力。我们的主要研究目标是急性到慢性疼痛的过渡和缓解慢性疼痛状态的治疗干预，成功识别口服活性过氧亚硝酸盐分解催化剂将解决许多已知由氮氧化应激导致的慢性疾病状态，包括糖尿病、动脉粥样硬化和帕金森氏症，从而对这些患者的生活质量产生重大影响。我们还表明，原型催化剂与选择性COXII抑制剂、非选择性COX-I抑制剂、类固醇和甲氨蝶呤的亚治疗水平具有高度的协同作用。因此，通过这种方法，我们可能能够大幅降低这些重要药物的剂量，以有效治疗疼痛，而不会产生或极大地减少副作用。 与公共卫生相关：目前用于治疗与炎症性疾病和关节炎相关的慢性疼痛的药物方案包括许多不同的作用机制，效果不明显，而且往往显示出不可接受的副作用。因此，基于对关键神经毒性物种过氧亚硝酸盐的催化分解而广泛有效地治疗慢性疼痛，将对患者产生广泛的有益影响。此外，口服活性过亚硝酸盐分解催化剂的鉴定将解决许多已知由氮氧化应激引起的慢性疾病状态，包括糖尿病、动脉粥样硬化和帕金森病，从而对这些患者的生活质量产生重大影响。

DESCRIPTION (provided by applicant): One third of Americans suffer from some form of chronic pain, (30% being resistant to analgesic therapy), making it a significant health problem with serious economic impact (estimated cost of approximately $100 billion annually). Chronic pain associated with complex regional pain syndromes is particularly difficult to manage. Chronic pain associated with inflammatory diseases such as rheumatoid arthritis is often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Current drug regimens are marginally effective and often display unacceptable side effects. Over the past decade, our multidisciplinary team has produced experimental results which clearly implicate the overproduction of peroxynitrite as a key mediator of inflammatory and chronic pain states in addition to the development of morphine-induced hyperalgesia and antinociceptive tolerance. Thus, the direct scavenging of this neurotoxic entity by small molecule drugs which act in enzyme-like catalytic fashion provides an unconventional approach to a completely novel analgesic strategy. The overriding goal is a broadly effective treatment for chronic pain associated with inflammatory diseases. Thus, a series of metal-charge-shielded metalloporphyrin and porphyrinoids with membrane penetration properties will be synthesized and screened as peroxynitrite decomposition catalysts. Pharmacokinetic and bioavailability studies will follow. Chemical entities displaying the highest catalytic activity with drug like properties will then be tested for analgesic efficacy and potency in 2 well established animal models of inflammation and arthritis While the main focus our research objective is in the transition of acute to chronic pain and therapeutic intervention to alleviate the chronic pain state, successful identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations. We have also shown that prototype catalysts act in a highly synergistic manner with subtherapeutic levels of selective COXII inhibitors, non-selective COX-I inhibitors, steroids, and methotrexate. Thus, through this approach we may be able to greatly lower the dosages of these important drugs for effective treatment of pain without or with greatly diminished side- effects. PUBLIC HEALTH RELEVANCE: The currently used drug regimens for the treatment of chronic pain associated with inflammatory diseases and arthritis, which encompass a number of varied mechanisms of action, are marginally effective and often display unacceptable side effects. Thus, a broadly effective treatment for chronic pain based upon the catalytic decomposition of the key neurotoxic species, peroxynitrite, would have wide-ranging beneficial effects for patients. In addition, the identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations.