Scope: KYNETIC-A highly selective mPGES-1 inhibitor as an effective and non-addictive analgesic

Pain is a significant public health problem costing $560-$635 Billion annually in the US. Opioid is a class of pain medications with the capacity to deliver pain relief, but with high potential for abuse and physical dependence. The other major class of analgesics in clinical use are nonsteroidal anti-inflammatory drugs (NSAIDs) that are non-addictive. However, traditional NSAIDs (including celecoxib, a selective COX-2 inhibitor) have significant cardiovascular, cerebrovascular, and gastrointestinal risks. Interestingly, microsomal prostaglandin E synthase-1 (mPGES-1) is the most promising, ideal target for next-generation NSAIDs, and various mPGES-1 inhibitors have been reported in the literature. Unfortunately, none of the previously reported potent inhibitors of human mPGES-1 have shown to also be potent against mouse/rat mPGES-1, which prevents using well-established wild-type mouse/rat models of inflammation and pain for preclinical efficacy studies. Nevertheless, we have successfully discovered a novel class of potent mPGES-1 inhibitors (including BAR002 as our current lead) that are potent for not only human mPGES-1, but also mouse and rat mPGES- 1. BAR002 is also highly selective for mPGES-1 over COX-1/2 and orally bioavailable, enabling preclinical testing using well-established wild-type mouse/rat models of inflammation and pain. Our further in vivo studies have confirmed that, compared to celecoxib, BAR002 is indeed much safer and more effective. In this project, we will test BAR002 and its analogs in various animal models to identify an optimal mPGES- 1 inhibitor drug candidate with a suitable oral formulation for safely and effectively treating inflammation and various types of pain. The specific milestones of the proposed entire project: (1) Confirm that BAR002 is a truly promising lead. Go/no-go decision: Go if BAR002 is effective in all the animal models of pain tested. (2) Perform lead optimization and identify the top-two compounds with their optimal dosing vehicles. Go/no-go decision: Go if top-two compounds (that may include BAR002) along with their optimal dosing vehicles have been identified. (3) Examine the PK/PD profiles and identify the best compound with the optimal oral dosing vehicle. Go/nogo decision: Go if the top compound with an optimal dosing vehicle has been identified and the corresponding PK/PD profile has been determined (4) Determine the maximum tolerated dose (MTD) and minimum effective dose (MED) of the optimal compound with the optimal dosing vehicle in each pain model used. Go/no-go decision: Go if MTD > 3 g/kg and if the MED-associated human equivalent dose (HED) . 200 mg for all pain models tested. Achieving these milestones will make the optimal mPGES-1 inhibitor ready for subsequent drug development efforts including cGMP (current Good manufacture Practice) manufacturing, IND (Investigational New Drug)-enabling studies, and clinical trials. Our team has extensive experience in rational design, discovery, and development of novel drug candidates, including two tested in Phase II clinical trials.