Format

Send to

Choose Destination
Bioorg Med Chem. 2015 Nov 15;23(22):7332-9. doi: 10.1016/j.bmc.2015.10.033. Epub 2015 Oct 24.

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

Author information

1
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
2
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
3
Hygiene Detection Center, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: yxmjp@sina.com.
4
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.

Abstract

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 8 j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50=410 nM) with rolipram. More interestingly, compound 8 g, 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 8 g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules.

KEYWORDS:

Catechol-based benzamides; Molecular docking; Phosphodiesterase 4D inhibitors; Selectivity; Structure–activity relationship

PMID:
26526739
DOI:
10.1016/j.bmc.2015.10.033
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center