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

Somatostatin receptor-4 (SST 4 ) is highly expressed in brain regions affiliated with learning and memory. SST 4 agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST 4 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 SST 4 binding affinity, activity, and selectivity. Thirty-five compounds showed low nanomolar range SST 4 binding affinity, 12 having a K i < 1 nM. These compounds showed >500-fold affinity for SST 4 as compared to SST 2A . SST 4 activities were consistent with the respective SST 4 binding affinities (EC 50 < 10 nM for 34 compounds). Compound 208 (SST 4 K i = 0.7 nM; EC 50 = 2.5 nM; >600-fold selectivity over SST 2A ) display a favorable physiochemical profile, and was advanced to learning and memory behavior evaluations in the senescence accelerated mouse-prone 8 model of AD-related cognitive decline. Chronic administration enhanced learning with i.p. dosing (1 mg kg −1 ) compared to vehicle. Chronic administration enhanced memory with both i.p. (0.01, 0.1, 1 mg kg −1 ) and oral (0.01, 10 mg kg −1 ) dosing compared to vehicle. This study identified a novel series of SST 4 agonists with high affinity, selectivity, and biological activity that may be useful in the treatment of AD. 3,4,5-Trisubstituted-1,2,4-triazole somatostatin receptor-4 agonist SAR.