在Eur J Med Chem和ACS Chem Neurosci上发表研究论文
近日，神经药理及新药发现课题组周中振副教授/徐江平教授以共同通讯作者连续在Eur J Med Chem和ACS Chem Neurosci.上发表了题为“Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings”和“Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses”两篇研究论文。 神经炎症通过影响神经内分泌及神经递质(如去甲肾上腺素及5-羟色胺等)的代谢参与神经精神疾病的发病过程。磷酸二酯酶4 （PDE4）是良好的抗神经炎症的靶点，但现有PDE4抑制剂普遍存在严重致呕吐的不良反应，致使临床应用受阻。针对这一问题，近日，周中振副教授/徐江平教授研究团队设计合成了一系列N-烷基邻苯二酰胺类化合物。通过PDE4酶抑制活性筛选得到数个目标化合物，这些化合物对PDE4的选择性高出其他PDE亚型1000余倍以上。在小胶质细胞中，通过LPS诱导神经炎症，发现得到的化合物具有良好的抗炎作用，药代动力学研究显示这些化合物可以透过血脑屏障，进入中枢神经系统。动物实验显示这些化合物能产生显著的抗抑郁效应，但不影响动物的自主活动。尤其重要的是在小鼠翻正反射及比格犬致呕吐实验中均未见呕吐样反应，显示出极大的开发价值及临床应用价值。
此两篇论文受到国家自然科学基金-广东联合基金、国家自然科学基金、新药创制重大专项、广东省科技计划、广东省高等学校优秀青年教师培育计划等基金资助。Eur J Med Chem为药物化学2区杂志， IF=3.902；ACS Chem Neurosci为小类药物化学1区杂志，IF=4.348。
1. Zhou ZZ, Ge BC, Zhong QP, Huang C, Cheng YF, Yang XM, Wang HT, Xu JP. Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings. Eur J Med Chem. 2016, 124:372-379.
In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.
2. Zhou ZZ, Cheng YF, Zou ZQ, Ge BC, Yu H, Huang C, Wang HT, Yang XM, Xu JP. Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses. ACS Chem Neurosci. 2016 Oct 3. [Epub ahead of print]
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 side effect of 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, ten compounds displayed sub-micromolar 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.