Abstract
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.