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 showed >500-fold affinity for SST₄ as compared to SST_2A. SST₄ activities were consistent with the respective SST₄ binding affinities (EC₅₀ < 10 nM for 34 compounds). Compound 208 (SST₄K_i = 0.7 nM; EC₅₀ = 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 SST₄ agonists with high affinity, selectivity, and biological activity that may be useful in the treatment of AD.