Design, synthesis and evaluation of small molecules as inhibitors of plasminogen activator inhibitor-1

<p>Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. Excessive levels of PAI-1 inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), which regulates fibrinolysis as well as the development of different pathological diseases like obesity, metabolic syndrome, tumor invasion and metastasis, and coronary heart disease. Currently, there is no Food and Drug Administration approval for inactivating higher levels of PAI-1. Therefore, PAI-1 is considered an attractive drug target. Due to PAI-1’s different structural conformations and multiple binding domains, development of PAI-1 inhibitors is a challenging situation. In this research study, we describe the synthesis and evaluation of novel low molecular weight amides containing various moieties, including para-chlorobenzyl, polyphenol, oxindole, or isatin-based units. By changing the architectural scheme of these compounds we hope to effectively change the potency of our inhibitors, and will be able to develop a structure-activity relationship that will allow us to design a more potent small molecule as a PAI-1 inhibitor. Therefore, the synthesis and structure-activity relationship of those novel small molecules are discussed in this paper.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Open Access Thesis

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2014

Author dc:creator

• Weerakoon, Darshani Avanthi

Contributors dc:contributor

• Cory D. Emal, PhD, Chair
• Gregg Wilmes, PhD
• Ingo Janser, PhD

• Drug design
• Drug synthesis
• Isatin
• Oxindole
• PAI-1
• Small molecules
• Chemistry

Repository record dc:identifier

https://commons.emich.edu/theses/705

OAI identifier oai:identifier

oai:commons.emich.edu:theses-2084