Pain Relieving Properties of Analgesic Metabolites

描述（由申请人提供）：对乙酰氨基酚广泛用于轻度至中度疼痛的治疗。即便如此，对乙酰氨基酚在摄入大剂量或长期使用较小剂量后仍可能导致肝毒性，特别是在老年人中，当肝功能受损或同时饮酒时。对乙酰氨基酚引起的肝损伤不是由于药物本身，而是由于形成有毒代谢物，通常可以通过与谷胱甘肽结合来解毒。然而，随着急性过量或长期使用，谷胱甘肽储存被耗尽，有毒代谢物与肝细胞蛋白结合并导致肝坏死。我们一直在探索一系列新的和专有的对乙酰氨基酚衍生物，其中的先导化合物（SCP-1）具有良好的口服疗效，几乎没有肝毒性。由于SCP-1向对乙酰氨基酚的代谢转化是最小的，SCP-1通过与对乙酰氨基酚不同的途径发挥作用，SCP-1不是对乙酰氨基酚的“前药”。该I期申请探索了两种主要的SCP-1代谢物是否具有镇痛活性而不具有肝毒性，以（1）了解SCP-1药物作用的机制，以及（2）确定开发这些代谢物用于目标人群的可行性，其中镇痛药物的生物转化，包括对乙酰氨基酚或SCP-1，可能降低治疗活性和/或增加不希望的副作用。它将确定两种SCP-1代谢物在两种动物疼痛模型中的镇痛效果是否与SCP-1或对乙酰氨基酚相当或更好。它还将确定慢性和急性给药后的肝毒性。如果SCP-1代谢物显示出镇痛特性而没有肝毒性，则将在II期SBIR下提出进一步的药物开发，最终在具有影响药物生物转化为活性代谢物的高水平因素的特殊人群中进行临床试验，包括患有肝病，营养不良，肥胖症，遗传决定的多态性，同时使用抑制代谢酶的药物，饮酒，和老年人。

DESCRIPTION (provided by applicant): Acetaminophen is used extensively in the management of mild to moderate pain. Even so, acetaminophen can cause hepatotoxicty after ingestion of large doses or from chronic use of smaller doses, particularly in the elderly, when liver function is compromised, or with concurrent alcohol use. Acetaminophen-induced liver injury is due not to the drug itself but to the formation of a toxic metabolite that normally would be detoxified by conjugation with glutathione. However, with an acute overdose or chronic use, glutathione stores are depleted and the toxic metabolite binds to liver cell proteins and causes hepatic necrosis. We have been exploring a series of new and proprietary acetaminophen derivatives, in which the lead compound (SCP-1) has good oral efficacy and produces little if any hepatotoxicity. Because the metabolic conversion of SCP-1 to acetaminophen is minimal, SCP-1 has its effects through different pathways than acetaminophen and SCP-1 is not a 'pro-drug' of acetaminophen. This Phase I application explores whether two major SCP-1 metabolites possess analgesic activity without hepatotoxicity in order to (1) understand the mechanisms of SCP-1 drug action, and (2) determine the feasibility of developing these metabolites for use in targeted populations in which the biotransformation of analgesic medications, including acetaminophen or SCP-1, could reduce therapeutic activity and/or increase the unwanted side-effects. It will determine whether the two SCP-1 metabolites have analgesic effects comparable to or better than SCP-1 or acetaminophen in two animal models of pain. It will also determine hepatotoxicity after chronic and acute dosing. If the SCP-1 metabolites show analgesic properties without hepatotoxicity, further drug development will be proposed under a Phase II SBIR with eventual clinical trials in special populations that have high levels of factors that influence the biotransformation of drugs into active metabolites, including patients with liver disease, malnutrition, obesity, genetically determined polymorphisms, concurrent use of drugs that inhibit metabolic enzymes, alcohol use, and the elderly.