Multitarget Approach for the Treatment of Alzheimer’s Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer’s disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).本研究报道了一系列双靶点磷酸二酯酶9（PDE9）与组蛋白去乙酰化酶（HDAC）抑制剂，这类化合物被开发为药理学工具化合物，用于评估这两个靶点在阿尔茨海默病（AD）中的作用。这些新型抑制剂的设计兼顾了已知选择性PDE9抑制剂的关键药效团特征与优势化学结构，其携带的锌结合基团包括羟肟酸与邻氨基苯胺类，可作用于HDAC靶点。该类取代基基于本课题组的理性设计准则与前期研究成果进行筛选，旨在探索多样化的HDAC选择性谱——涵盖泛HDAC、HDAC6选择性以及I类选择性，相关选择性已通过生化筛选得到验证。我们测定了这类化合物诱导组蛋白与微管蛋白乙酰化、以及环腺苷酸应答元件结合蛋白（CREB）磷酸化的功能活性，这是后续开展完整的体外吸收、分布、代谢与排泄（ADME）研究以及体内脑穿透性表征的必要前提。其中化合物31b是一款兼具良好脑通透性的HDAC6选择性抑制剂，被选用于评估这类首创类抑制剂的体内药效，并探究其作用机制（MoA）。