title: Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.
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.
authors.affiliation: Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Zhou
authors.affiliation: Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bing-Chen
authors.initials: BC
authors.lastname: Ge
authors.affiliation: Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiu-Dong
authors.initials: XD
authors.lastname: Shi
authors.affiliation: Hygiene Detection Center, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: yxmjp@sina.com.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Yang
authors.affiliation: Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Xu
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D002396:Catechols / Q000737:chemistry*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002396:Catechols; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C034221:catechol
keywords: Catechol-based benzamides; Molecular docking; Phosphodiesterase 4D inhibitors; Selectivity; Structure–activity relationship