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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• 作者：Zhong-Zhen Zhou ; Yu-Fang Cheng ; Zheng-Qiang Zou ; Bing-Chen Ge ; Hui Yu ; Cang Huang ; Hai-Tao Wang ; Xue-Mei Yang ; Jiang-Ping Xu
• 刊名：ACS Chemical Neuroscience
• 出版年：2017
• 出版时间：January 18, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：135-146
• 全文大小：593K
• ISSN：1948-7193

文摘

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.