Dissertation/Thesis Abstract

Design, Synthesis, and Evaluation of 3,4,5-Trisubstituted-1,2,4-Triazoles as Selective SST4 Agonists for the Treatment of Alzheimer's Disease
by Kukielski, Stephen, M.S., Southern Illinois University at Edwardsville, 2018, 152; 10790696
Abstract (Summary)

This research investigates the lead optimization of 3,4,5-trisubstituted-1,2,4-triazoles as somatostatin subtype 4 (SST4) agonists to alleviate the progression and symptoms of Alzheimer’s disease. Alzheimer’s pathology has been associated with the aggregation of Amyloid-β (Aβ) plaques in the brain. We hypothesize that the SST4 agonists described herein will enhance the clearance of Aβ plaques through the activation of SST 4 leading to an increase in neprilysin, an endopeptidase associated with plaque degradation and clearance. In this research, the affinity and selectivity of functionalized triazole analogues for the somatostatin SST 4 receptor were explored. The resulting structure activity relationship (SAR) information from these studies is currently being used to determine optimal substitution of candidate molecules and improve their drug-like properties (e.g. metabolic stability and solubility). Several new series of compounds were developed that were found to have high affinity and selectivity for the SST4 receptor (low to sub-nM Ki). In addition, selected molecules have been shown to have agonist properties in functional assays. Finally, we describe the development of a new modular and parallel-friendly synthetic route for the preparation of previously inaccessible arylthio-linked analogues. The compounds designed and synthesized during this research have not only been identified as potential candidates for increasing neprilysin levels, but have also aided in elucidating many aspects of selective SST4 receptor binding.

Indexing (document details)
Advisor: Neumann, William L.
Commitee: Crider, A. Michael, Witt, Kenneth
School: Southern Illinois University at Edwardsville
Department: Chemistry
School Location: United States -- Illinois
Source: MAI 57/06M(E), Masters Abstracts International
Subjects: Pharmaceutical sciences
Keywords: 3,4,5-Trisubstituted-1,2,4-Triazoles, Alzheimer's disease, Amyloid-beta plaques, Neprilysin, SST4 agonists, Somatostatin
Publication Number: 10790696
ISBN: 9780355987973
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