Development of a Highly Selective mPGES-1 Inhibitor as an Effective Non-Opioid Treatment of Chronic Pain

This investigation is focused on development of non-opioid therapies and methods for the treatment of chronic pain within the FY21 CPMRP IIRA Focus Areas, particularly development of a novel non-opioid pharmacological solution. According to the Centers for Disease Control and Prevention, “An estimated 20.4% (50.0 million) of U.S. adults had chronic pain”. Particularly, pain is the most common physical complaint affecting service members, with 50% of male and 75% of female veterans reporting chronic pain. Current therapies for chronic pain may be divided into three classes: opioid analgesics, non-steroidal anti- inflammatory drugs (NSAIDs), and anticonvulsants/antidepressants. As well known, opioids are a class of analgesics with the capacity to deliver pain relief by activating opioid receptors, particularly µ-opioid receptors. Unfortunately, while effective as analgesics, opioids are also associated with abuse and physical dependence potential. Currently available opioids also have other side effects including constipation, sexual dysfunction, and depression. NSAIDs have no abuse potential. However, traditional NSAIDs are minimally effective for neuropathic pain relief, and they have significant cardiovascular, cerebrovascular, and gastrointestinal risks. The serious side effects of anticonvulsants/antidepressants include somnolence and dizziness. So, a truly safe, effective, and non-addictive analgesic for chronic pain relief is an unmet clinical need. As well known, pain starts from tissue damage/injury and the corresponding inflammation response, and tissue damage always induces overproduction and release of the principal proinflammatory mediator, known as prostaglandin E2 (PGE2). It is crucial to effectively suppress the PGE2 overproduction under the inflammatory and pain conditions. The drugs targeting PGE2 overproduction are not associated with abuse potential. Unfortunately, traditional NSAIDs indirectly block not only PGE2 production, but also synthesis of all other physiologically required prostaglandins. The serious side effects of NSAIDs are associated with blocking synthesis of all these physiologically required prostaglandins. We aim to develop a truly safe, more effective non- opioid pain medication by specifically blocking the enzyme (known as microsomal prostaglandin E2 synthase-1 or mPGES-1) directly responsible for PGE2 overproduction, without blocking synthesis of the other physiologically required prostaglandins. For development of a next generation of anti-inflammatory drugs, various mPGES-1 inhibitors have been reported in the literature. Unfortunately, almost all of the previously reported mPGES-1 inhibitors bind in a non- conserved region of the active-site cavity with huge difference between human and mouse/rat. Hence, none of the previously reported potent inhibitors of human mPGES-1 has shown to also be a truly potent inhibitor of mouse or rat mPGES-1, which prevents using well-established mouse/rat models of inflammation and pain for preclinical studies. To overcome the problem, we have successfully designed and discovered a novel type of mPGES-1 inhibitors potent for mPGES-1 of various species (including human, mouse, and rat etc.) through structure-based rational design of compounds capable of binding in a conserved region of the active-site cavity (conserved across all species). Our novel mPGES-1 inhibitors (including our current lead BAR002) are also highly selective for mPGES-1 and orally bioavailable, enabling preclinical testing using the well-established wild-type mouse/rat models of inflammation and pain through both parenteral injection and oral administration for the first time. Built on our success in rational design and discovery of the unique, highly selective mPGES-1 inhibitors, we propose to further evaluate BAR002 and the more active mPGES-1 inhibitors in both male and female rodents (mice and rats) for their anti-inflammatory and analgesic effects in order to select the best one as a drug candidate ready for further preclinical and clinical drug development for treatment of chronic pain as well as acute pain. The interim outcomes of this investigation include: (1) Confirm that mPGES-1 is a truly feasible target for development of a novel type of analgesics to treat both acute and chronic pain including neuropathic pain; (2) confirm that the selective mPGES-1 inhibitors are highly effective for pain relief, without the abuse potential of opioids and without the serious side effects of traditional NSAIDs; and (3) identify the most promising mPGES- 1 inhibitor as a drug candidate for future further drug development. Accomplishment of this investigation will result in selection of a promising non-opioid drug candidate for treatment of chronic pain (as well as acute pain) with the highly desired efficacy and safety. The selected best non-opioid drug candidate will be ready for further drug development including current good manufacture practice (cGMP), formulation development, investigational new drug (IND)-enabling tests, and clinical trials (Phases I, II, and III) for chronic (and acute) pain relief before obtaining the FDA’s approval for clinical applications. So, this investigation will eventually lead to meeting and the unmet need of a truly safe and non- addictive pain medication and, thus, will be beneficial to all people with pain conditions.