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.
|Advisor:||Neumann, William L.|
|Commitee:||Crider, A. Michael, Witt, Kenneth|
|School:||Southern Illinois University at Edwardsville|
|School Location:||United States -- Illinois|
|Source:||MAI 57/06M(E), Masters Abstracts International|
|Keywords:||3,4,5-Trisubstituted-1,2,4-Triazoles, Alzheimer's disease, Amyloid-beta plaques, Neprilysin, SST4 agonists, Somatostatin|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be