Pain Relieving Properties of Analgesic Metabolites

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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.