Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.
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 IC50values 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.
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
Zhong-Zhen
ZZ
Zhou
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Bing-Chen
BC
Ge
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Qiu-Ping
QP
Zhong
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Chang
C
Huang
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Yu-Fang
YF
Cheng
Hygiene Detection Center, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: yxmjp@sina.com.
Xue-Mei
XM
Yang
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Hai-Tao
HT
Wang
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
Jiang-Ping
JP
Xu
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D017628:Microglia / Q000187:drug effects*; D062105:Molecular Docking Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D002396:Catechols; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C034221:catechol
Anti-neuroinflammation activity; Catecholamides; Molecular docking; Selective phosphodiesterase 4 inhibitors; Structure-activity relationship