COBRE Pilot: Evaluation of Highly Selective mPGES-1 Inhibotor, UK4b, as a Non-addictive Orofacial Pain Medication

Approximately 25 million Americans suffer daily from chronic pain. Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), such as Celecoxib, are currently prescribed for pain relief, the use of opioids leads to addiction, misuse and overdoses while chronic use of NSAIDs is associated with significant cardiovascular, cerebrovascular and gastrointestinal risks. Here we propose to test the efficacy of the novel mPGES-1 inhibitor, UK4b, developed in Dr. Zhan’s laboratory, in treating inflammatory and neuropathic pain. Unlike the COX inhibitor Celecoxib, UK4b acts specifically on the downstream pain associated branch of the COX pathway allowing for the analgesic properties of a COX inhibitor while mitigating the serious side effects associated with COX inhibitors. With COBRE funding, we will generate necessary preliminary data (demonstrating that UK4b is a promising lead compound) for an NIH R01 grant proposal. UK4b will serve as a promising compound for further lead optimization and in vivo studies using other animal models of inflammation and pain. In particular, starting from the molecular structure of UK4b, various analogs will be designed (via structure-based rational design), prepared, characterized, and tested in vitro and in vivo in order to obtain an optimized analog with the best possible overall in vivo profiles in terms of the anti-inflammatory and analgesic effects and safety.