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 (SST₄ K_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.

中文翻译：

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3,4,5-三取代-1,2,4-三唑的合成和构效关系：用于阿尔茨海默病治疗的高亲和力和选择性生长抑素受体4激动剂

生长抑素受体 4 (SST ₄ ) 在与学习和记忆相关的大脑区域中高度表达。SST ₄激动剂治疗可起到减轻阿尔茨海默病 (AD) 病理学的作用。本文介绍了 SST ₄激动剂先导优化的综合方法。通过包含计算方法、化学和临床前药理学的基于结构的设计策略的迭代循环，确定了具有生物功效的高亲和力和选择性激动剂。我们先前报道的命中 ( 4 )的 1,2,4-三唑衍生物显示出增强的 SST ₄结合亲和力、活性和选择性。35 种化合物显示出低纳摩尔范围的 SST ₄结合亲和力，12 种具有K _i < 1 nM。_{与 SST 2A}相比，这些化合物对 SST ₄的亲和力 > 500 倍。SST ₄活性与各自的 SST ₄结合亲和力一致（34 种化合物的 EC ₅₀ < 10 nM）。化合物208（SST ₄ K _i = 0.7 nM；EC _{50 = 2.5 nM；比 SST 2A}高 600 倍以上的选择性）显示出良好的物理化学特性，并在衰老加速小鼠易发 8 模型中用于学习和记忆行为评估AD 相关的认知能力下降。长期给药通过 ip 给药 (1 mg kg ^-1 ) 与车辆相比。与赋形剂相比，通过腹腔内给药（0.01、0.1、1mg kg ^-1）和口服（0.01、10mg kg ^{-1 ）给药，慢性给药增强了记忆力。}本研究确定了一系列具有高亲和力、选择性和生物活性的新型 SST ₄激动剂，可用于治疗 AD。