Alzheimer’s disease (AD) is the most common form of dementia and effects an estimated 44 million people worldwide. Current medications approved for the treatment of AD (acetylcholinesterase inhibitors and NMDA antagonists) are only palliative and do not change the course of disease progression. Thus, new therapeutic strategies that are disease modifying are desperately needed. In addition to strategies which prevent the formation of Aβ-derived pathologies, pathways which can enhance the degradation of Aβ oligomers and peptides are particularly exciting. The neuropeptide somatostatin is known to enhance the degradation of Aβ in the CNS through the downstream up-regulation of the endopeptidase neprilysin. Unfortunately, somatostatin levels in the CNS are significantly lowered in the aged and in AD patients. Somatostatin is a cyclic peptide with a short in vivo half-life, and thus, cannot be used as a direct therapeutic. To this end, selective somatostatin subtype 4 (SST4) agonists represent a novel class of therapeutic candidates for treating AD. Herein we report lead optimization studies of 3,4,5-trisubstituted-1,2,4-triazole class of SST4 agonists. The 1,2,4-triazole analogues were mainly synthesized through the condensation reaction of an acylhydrazide and a functionalized thioamide. Isothiocyanate chemistry was also investigated for the synthesis of 1,2,4-triazolethiol derivatives. An indolealkyl group, a propylimidazole, and, a benzyl group represent amino acid side-chain mimics appended to the triazole core. The structure-activity relationship (SAR) strategy for this study was to vary the benzyl and indole substituents while the propylimidazole group was held constant. The goals of the project were to improve the binding affinity, maintain selectivity, and enhance physiochemical and drug-like properties of the agonists. Several new selective, high affinity analogues, representing a good range of cLogP values, have been prepared and this work is described herein.
|Advisor:||Neumann, William L.|
|Commitee:||Crider, Michael, Lu, Yun|
|School:||Southern Illinois University at Edwardsville|
|School Location:||United States -- Illinois|
|Source:||MAI 56/06M(E), Masters Abstracts International|
|Keywords:||Alzheimer's disease, Medicinal chemistry, Somasotatin receptor subtype-4 receptor agonist|
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