Alzheimer’s disease (AD) is the most common form of dementia and effects an estimated 35 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. To this end, selective somatostatin subtype 4 (SST4) agonists represent a novel class of therapeutic candidates for treating AD. Herein we report lead identification and initial optimization studies of a novel and druggable class of small molecule SST4 agonists that rescue learning and memory deficits in transgenic mouse models of AD through this potential disease modifying mechanism of action. Synthesis, characterization, physiochemical properties, receptor binding/selectivity, receptor activity/function and in vivo proof of concept studies will be described.

Synthesis and SAR studies of somatostatin subtype-4 agonists for the treatment of Alzheimer’s disease

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.