Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure activity relationship study of catecholamides bearing aromatic rings

作者：Zhou, Zhong-Zhen^*; Ge, Bing-Chen; Zhong, Qiu-Ping; Huang, Chang; Cheng, Yu-Fang; Yang, Xue-Mei^*; Wang, Hai-Tao; Xu, Jiang-Ping^*

来源：European Journal of Medicinal Chemistry, 2016, 124: 372-379.

DOI：10.1016/j.ejmech.2016.08.052

• Catecholamides
• Selective phosphodiesterase 4 inhibitors
• Structure-activity relationship
• Molecular docking
• Anti-neuroinflammation activity

In this study, catecholamides (7a-1) 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-1 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-alpha production in microglia.

• 出版日期2016-11-29
• 单位南方医科大学