Abstract |
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.
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Authors | Zhong-Zhen Zhou, Bing-Chen Ge, Qiu-Ping Zhong, Chang Huang, Yu-Fang Cheng, Xue-Mei Yang, Hai-Tao Wang, Jiang-Ping Xu |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 124
Pg. 372-379
(Nov 29 2016)
ISSN: 1768-3254 [Electronic] France |
PMID | 27597413
(Publication Type: Journal Article)
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Copyright | Copyright © 2016 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Anti-Inflammatory Agents
- Catechols
- Phosphodiesterase 4 Inhibitors
- Cyclic Nucleotide Phosphodiesterases, Type 4
- catechol
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Topics |
- Anti-Inflammatory Agents
(chemical synthesis, chemistry, metabolism, pharmacology)
- Catechols
(chemical synthesis, chemistry, metabolism, pharmacology)
- Cell Line
- Chemistry Techniques, Synthetic
- Cyclic Nucleotide Phosphodiesterases, Type 4
(chemistry, metabolism)
- Drug Design
- Humans
- Microglia
(drug effects)
- Molecular Docking Simulation
- Phosphodiesterase 4 Inhibitors
(chemical synthesis, chemistry, metabolism, pharmacology)
- Protein Conformation
- Structure-Activity Relationship
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