Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical Sciences


Molecular and Systems Pharmacology

Research Advisor

Jianxiong Jiang, PhD


Wei Li, PhD; Clinton Stewart, PharmD; Thirumalini Vaithianathan, PhD; Chao-Yie Yang, PhD


COX pathway, inflammatory, mPGES-1 inhibitors, Prostaglandins


Prostaglandin E2 (PGE2) is a potent proinflammatory lipid signaling molecule produced downstream of the cyclooxygenase (COX) cascade. The COX pathway has long been implicated for its role in inflammation, with drugs like aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) non-selectively targeting the upstream COX enzymes to suppress inflammation. However, despite displaying potent anti-inflammatory effects it has been demonstrated that when taken chronically, NSAIDs can cause gastrointestinal bleeding. COX-2 selective inhibitors (COXIBs) were then developed to combat the gastrointestinal bleeding induced by nonselective NSAIDs by specifically inhibiting the COX enzyme most infamous for its role in inflammation. Yet, soon after entering the market it became apparent that COXIBs provoked even more deleterious cardiovascular side effects. Thus, there is a critical and urgent need for novel anti-inflammatory therapeutics targeting the COX cascade that circumvent the adverse effects of chronically targeting COX. Microsomal prostaglandin E synthase-1 (mPGES-1) is the major producer of PGE2 during inflammation and therefore represents a more specific therapeutic target to combat inflammation. Although a promising target, mPGES-1 inhibitors have been difficult to develop due to the interspecies differences that exist between the human and murine enzyme, creating a hurdle in the preclinical drug development of mPGES-1 inhibitors. Utilizing the well-known dual species mPGES-1 inhibitor C3 as our parent compound, we developed a series of 20 novel mPGES-1 inhibitors by employing a scaffold hopping design approach. We selected the benzothiazole and phenyl-thiazole scaffolds to replace the benzimidazole scaffold within C3, to increase lipophilicity with the notion of increasing blood brain barrier penetration. From our primary screen at 10 µM we identified two inhibitors namely compound 11 (UT-11) and compound 19, representing our novel scaffolds that were able to significantly suppress PGE2 production in both human (SK-N-AS) and murine (BV2) cells better than their parent compound (C3). To follow up on our initial screen IC¬¬50 values of UT-11 and compound 19 were calculated. We obtained 0.10 and 2.00 μM for UT-11 and 0.43 and 1.55 μM for compound 19 against human and murine cells, respectively. These results, coupled with in vitro anti-inflammatory effects and pharmacokinetic data of UT-11 lead us to select UT-11 for in vivo evaluation. Using an lipopolysaccharide (LPS)-induced inflammation model we found that treatment with UT-11 following exposure to LPS (3mg/kg) was able to significantly suppress pro-inflammatory mediators in the hippocampus, but not in the kidney. It is important to note that the anti-inflammatory effects of UT-11 were dependent on mPGES-1 expression, thus underscoring the specificity of UT-11. Taken together these results demonstrate the potential utility of UT-11 in treating other neuroinflammatory diseases such as epilepsy and stroke, which should be investigated in future studies.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.




2023-017-Sluter-DOA.pdf (151 kB)
Declaration of Authorship

Available for download on Sunday, July 06, 2025