RESUMEN
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 SST2A. SST4 activities were consistent with the respective SST4 binding affinities (EC50 < 10 nM for 34 compounds). Compound 208 (SST4 K i = 0.7 nM; EC50 = 2.5 nM; >600-fold selectivity over SST2A) 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.
RESUMEN
Allergic diseases are the most common conditions in children and the second most frequent in adults. Currently, there are two well-defined generations of antihistamines, those belonging to first generation, with inherent side effects such as drowsiness and anticholinergic effects. These side effects are often attributed to their high lipophilicity and high affinity for brain H1 receptors. The ebastine is a modern antihistaminic drug belongs to the second generation and has lower lipophilicity, which diminish the undesirable side effects. To ensure the quality, efficacy, safety, and effectiveness of ebastine drug products, efficient and reliable analytical methods are mandatory. Besides official compendial methods, alternative methods are often developed and used in quality control of pharmaceuticals as well as in pharmacokinetic studies. In this work, we present a critical review on characteristics, physicochemical properties, and analytical methods applied in the analysis of ebastine.
