Synthesis and structure-activity relationships of 3,4,5-trisubstituted-1,2,4-triazoles: high affinity and selective somatostatin receptor-4 agonists for Alzheimer's disease treatment.

ABSTRACT: Somatostatin receptor-4 (SST₄) is highly expressed in brain regions affiliated with learning and memory. SST₄ agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST₄ agonist lead optimization is presented herein. High affinity and selective agonists with biological efficacy were identified through iterative cycles of a structure-based design strategy encompassing computational methods, chemistry, and preclinical pharmacology. 1,2,4-Triazole derivatives of our previously reported hit (4) showed enhanced SST₄ binding affinity, activity, and selectivity. Thirty-five compounds showed low nanomolar range SST₄ binding affinity, 12 having a K _i < 1 nM. These compounds s

SUBMITTER: Neumann WL 

PROVIDER: S-EPMC8372316 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature