Date Approved

2019

Degree Type

Open Access Senior Honors Thesis

Department

Chemistry

First Advisor

Cory Emal

Second Advisor

Hedeel Evans

Third Advisor

Deborah Heyl-Clegg

Abstract

Plasminogen activator inhibitor type-I (PAI-I ) is a serpin superfamily member protein that acts as the major inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). At physiological levels, PAI-I plays an active role in regulating fibrinolysis, the process of normal blood clot degradation. Pathological levels of PAI-I have been linked to multiple health ailments: fibrosis, heart disease, cancer, and obesity. In recent years, PAI-1 has been the subject of targeted drug design. In this study, we identified a class of polyphenol compounds as the most capable of maintaining its inhibitory efficiency against vitronectin bound PAI-I in buffer and plasma. Additionally, a previously reported class of biphenyl amide PAI-I inhibitors was structurally probed to determine the pharmacophore. We provide evidence supporting the anti-PAI-I pharmacophore as the carboxylic acid moiety, observing modifications to this group significantly reduces potency. Furthermore, to assess if the in vivo metabolites of the biphenyl amides were active against PAl-1, structurally inspired metabolites were tested and found to yield no activity.

Included in

Chemistry Commons

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