Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships

Publication date: Available online 24 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Zhong-Zhen Zhou, Bing-Chen Ge, Yu-Fang Chen, Xiu-Dong Shi, Xue-Mei Yang, Jiang-Ping Xu
In this study, a series of catechol-based amides (8a–n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a–n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8j with a short amide linker (–CONHCH2–) displayed comparable PDE4CAT inhibitory activity (IC50 = 410 nM) with rolipram. More interestingly, compound 8g, a potent and selective PDE4D inhibitor (IC50 = 94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8g forms three extra H-bonds with the N–H of residue Asn487 and two water molecules.

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