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Dissertation/Thesis Abstract

Lead Optimization of Triazole-Based Somatostatin Subtype-4 Agonist for the Treatment of Alzheimer’S Disease
by Frare, Rafael F., M.S., Southern Illinois University at Edwardsville, 2020, 107; 27838098
Abstract (Summary)

Alzheimer’s disease (AD) is considered the most common form of dementia, affecting around 5.8 million Americans and about 30 million people around the globe. At present, we do not have the tools to accurately identify the different stages of the disease. In addition, current treatments are only symptomatic and lack the capacity to stop the progression of the disease. Thus, new strategies that help prevent the worsening of this condition are desperately needed. While the cause of AD is still largely unknown, most current research has focused on the increased production of amyloid beta (A) peptide aggregates in the brains of AD patients. The association of increase A peptide aggregation as insoluble plaques with disease progression is known as the amyloid hypothesis. To this end, effecting the clearance Aβ plaques may be a useful strategy for halting AD progression. Somatostatin has been shown to up-regulate the levels of the enzyme neprilysin, and endopeptidase that degrades Aβ peptide through the somatostatin subtype 4 (SST4) receptor. Unfortunately, somatostatin levels are considerably lowered with age and even more in AD affected individuals. Due to its peptidic nature, somatostatin cannot be used directly as a chronic orally delivered therapeutic agent. Therefore we have hypothesized that selective non-peptide SST4 agonists may show promise in treating AD. Herein, the optimization studies of a 3,4,5-trisubstituted-1,2,4-triazoles class of SST4 agonists is presented. Triazole-based SST4 agonists were synthesized by the condensation reaction of an acylhydrazide and functionalized thioamide or isocyanate precursors. Structure-activity-relationship (SAR) studies will be presented herein. The required 4-aminopropylimidazole group was held constant and the 3-benzyl and 5-indolealkyl groups were varied in order to improve selectivity, physicochemical properties, binding affinity and drug-like characteristics. As a result, several new promising analogs with improved affinity and selectivity have been identified.

Indexing (document details)
Advisor: Neumann, William L.
Commitee: Crider, Michael A., Witt, Kenneth A.
School: Southern Illinois University at Edwardsville
Department: Pharmaceutical Sciences
School Location: United States -- Illinois
Source: MAI 81/12(E), Masters Abstracts International
Subjects: Pharmaceutical sciences
Keywords: Alzheimer’s disease, Dementia, Somatostatin
Publication Number: 27838098
ISBN: 9798645480752
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