Tags

Type your tag names separated by a space and hit enter

Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships.
Bioorg Med Chem. 2015 Nov 15; 23(22):7332-9.BM

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Zhou ZZ
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
Ge BC
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Chen YF
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Shi XD
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Yang XM
Hygiene Detection Center, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: yxmjp@sina.com.
Xu JP
Neuropharmacology Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.

MeSH

AmidesBinding SitesCatalytic DomainCatecholsCyclic Nucleotide Phosphodiesterases, Type 4Drug DesignEnzyme ActivationHumansHydrogen BondingInhibitory Concentration 50IsoenzymesMolecular Docking SimulationPhosphodiesterase InhibitorsProtein BindingStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26526739

Citation

Zhou, Zhong-Zhen, et al. "Catecholic Amides as Potential Selective Phosphodiesterase 4D Inhibitors: Design, Synthesis, Pharmacological Evaluation and Structure-activity Relationships." Bioorganic & Medicinal Chemistry, vol. 23, no. 22, 2015, pp. 7332-9.
Zhou ZZ, Ge BC, Chen YF, et al. Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships. Bioorg Med Chem. 2015;23(22):7332-9.
Zhou, Z. Z., Ge, B. C., Chen, Y. F., Shi, X. D., Yang, X. M., & Xu, J. P. (2015). Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships. Bioorganic & Medicinal Chemistry, 23(22), 7332-9. https://doi.org/10.1016/j.bmc.2015.10.033
Zhou ZZ, et al. Catecholic Amides as Potential Selective Phosphodiesterase 4D Inhibitors: Design, Synthesis, Pharmacological Evaluation and Structure-activity Relationships. Bioorg Med Chem. 2015 Nov 15;23(22):7332-9. PubMed PMID: 26526739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships. AU - Zhou,Zhong-Zhen, AU - Ge,Bing-Chen, AU - Chen,Yu-Fang, AU - Shi,Xiu-Dong, AU - Yang,Xue-Mei, AU - Xu,Jiang-Ping, Y1 - 2015/10/24/ PY - 2015/09/18/received PY - 2015/10/22/revised PY - 2015/10/23/accepted PY - 2015/11/4/entrez PY - 2015/11/4/pubmed PY - 2016/8/19/medline KW - Catechol-based benzamides KW - Molecular docking KW - Phosphodiesterase 4D inhibitors KW - Selectivity KW - Structure–activity relationship SP - 7332 EP - 9 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 23 IS - 22 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/26526739/Catecholic_amides_as_potential_selective_phosphodiesterase_4D_inhibitors:_Design_synthesis_pharmacological_evaluation_and_structure_activity_relationships_ DB - PRIME DP - Unbound Medicine ER -