Author ORCID Identifier

https://orcid.org/0009-0006-8633-482X

Date Available

4-24-2025

Year of Publication

2023

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Chang-Guo Zhan

Second Advisor

Dr. Charles D Loftin

Abstract

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease is a deadly, permanent ballooning of the aortic artery. It often goes undiagnosed until a late stage where associated rupture has a high mortality rate. Surgery is the only option available to patients, but it is risky. There are currently no FDA-approved pharmacological treatments for AAA available. Historically, drugs that have been examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments have been unable to reach the clinic, stalling out in pre-clinical studies. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting.

Overall, current research stresses the importance of both centralized antiinflammatory drug targets and rigor of translatability. Notably, microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. To this end, it is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment. The Zhan Lab previously identified mPGES-1 inhibitors as potential anti-inflammatory drug candidates through two methods: structure-based rational design of novel small molecules and repurposing of FDA-approved drugs through computational modeling. The purpose of this work was to assess the capability of these lead mPGES-1 inhibitors to alter growth of AAA in the angiotensin (Ang)II-induced mouse model. We have shown successful implementation of a prevention-based treatment and more importantly, late-stage interventional drug treatment to modulate growth of AAA in this model. Additional studies supported the structure-activity relationship profile of our compounds and their potential translation into the clinical setting. Our results provide evidence supporting the use of mPGES-1 inhibitors as interventional treatment of AAA.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.073

Funding Information

This work was supported in part by funding from the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy and the National Institutes of Health [Grant P20 GM130456]. Funding was also provided as startup funds from the University of Kentucky College of Pharmacy and support from the Pharmaceutical Sciences Excellence in Graduate Achievement Fellowship from the University of Kentucky College of Pharmacy. Support was also provided by the Investigator-Initiated Research Award W81XWH2211,000 (to Dr. Chang-Guo Zhan and Dr. Fang Zheng) from the U.S. Department of Defense (DoD) Chronic Pain Management Research Program (CPMRP) and an award (to Dr. Fang Zheng and Dr. Chang-Guo Zhan) from the Kentucky Network for Innovation & Commercialization (KYNETIC) program associated with National Institute of Health grant U01 HL152392. Research reported in this publication from a COBRE Research Core was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [Grant P30 GM127211]. Research reported here was also supported by the University of Kentucky Cardiovascular Research Priority Area and their Ultrasound Core Facility.

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Available for download on Thursday, April 24, 2025

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