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

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.
AuthorsZhong-Zhen Zhou, Bing-Chen Ge, Qiu-Ping Zhong, Chang Huang, Yu-Fang Cheng, Xue-Mei Yang, Hai-Tao Wang, Jiang-Ping Xu
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 124 Pg. 372-379 (Nov 29 2016) ISSN: 1768-3254 [Electronic] France
PMID27597413 (Publication Type: Journal Article)
CopyrightCopyright © 2016 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Anti-Inflammatory Agents
  • Catechols
  • Phosphodiesterase 4 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • catechol
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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