Author ORCID Identifier

https://orcid.org/0000-0002-5216-669X

Year of Publication

2018

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department

Chemistry

First Advisor

Dr. Dong-Sheng Yang

Second Advisor

Dr. Chang-Guo Zhan

Abstract

As the principal pro-inflammatory prostanoid, prostaglandin E2 (PGE2) serves as mediator of pain and fever in inflammatory reactions. The biosynthesis of PGE2 starts from arachidonic acid (AA). Cyclooxygenase (COX)-1 and/or COX-2 converts AA to prostaglandin H2 (PGH2), and PGE2 synthases transform PGH2 to PGE2. Current mainstream approach for treating inflammation-related symptoms remains the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). As both categories shut down the biosynthesis of all downstream prostanoids, their application renders several deleterious effects including gastrointestinalulceration and cardiovascular risk. Microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors, specifically blocking the production of inflammation-related PGE2, are expected to reduce the adverse effects while retain the anti-inflammation activity. Although several compounds have been reported, only a few have entered clinical trials and none was on the market. Particularly, most of the reported human mPGES-1 inhibitors were not active for wild-type mouse/rat mPGES-1 enzymes, which prevents using the well-established mouse/rat models of inflammation in preclinical studies. Therefore, we expect our designed inhibitors to also be potent against mouse mPGES-1 and thus is suitable for preclinical testing in wild-type mice.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2018.395

Funding Information

This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grants CHE-1111761 and MRI grant CHE-1625732), and the National Institutes of Health via the National Center for Advancing Translational Sciences (UL1TR001998) grant.

Available for download on Friday, October 23, 2020

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