Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses.
Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses.
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DOI：
10.1021/acschemneuro.6b00271
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发表时间：
2017-01
影响因子：
5
通讯作者：
Zhong-Zhen Zhou;Yufang Cheng;Zhengqiang Zou;Bing-Chen Ge;Hui Yu;Cang Huang;Hai-Tao Wang;Xue-Mei Yang;Jiangping Xu
中科院分区：
文献类型：
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作者：
Zhong-Zhen Zhou;Yufang Cheng;Zhengqiang Zou;Bing-Chen Ge;Hui Yu;Cang Huang;Hai-Tao Wang;Xue-Mei Yang;Jiangping Xu
涉及神经炎症的抑郁症是最常见的致残和危及生命的精神疾病之一。磷酸二酯酶4（PDE 4）抑制剂产生有效的抗抑郁样和认知增强作用。然而，它们的临床效用受限于它们的主要副作用呕吐。为了获得具有抗抑郁和抗神经炎症潜力以及较少呕吐的更具选择性的PDE 4抑制剂，我们通过用烷基侧链修饰我们的热门化合物FCPE 07的4-甲氧基苄基，设计并合成了一系列N-烷基儿茶酚酰胺。在这些化合物中，10种化合物显示亚微摩尔IC 50值在中至低纳摩尔范围内。此外，带有异丙基的4-二氟甲氧基苯甲酰胺10 g和10 j表现出最高的PDE 4抑制活性，IC 50值在低纳摩尔范围内，对PDE 4具有更高的选择性（分别是其他PDE的约5000倍和2100倍）。此外，化合物10 j显示出抗神经炎症潜力、有希望的抗抑郁样作用以及在0.8mg/kg下在180分钟内呕吐的零发生率。
Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less emesis, we designed and synthesized a series of N-alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain. Among these compounds, 10 compounds displayed submicromolar IC50 values in the mid- to low-nanomolar range. Moreover, 4-difluoromethoxybenzamides 10g and 10j, bearing isopropyl groups, exhibited the highest PDE4 inhibitory activities, with IC50 values in the low-nanomolar range and with higher selectivities for PDE4 (approximately 5000-fold and 2100-fold over other PDEs, respectively). Furthermore, compound 10j displayed anti-neuroinflammation potential, promising antidepressant-like effects, and a zero incidence rate of emesis at 0.8 mg/kg within 180 min.