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Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors. 2018

Yixian Liao, and Yiming Guo, and Sumei Li, and Lei Wang, and Yongmei Tang, and Tianmiao Li, and Weihao Chen, and Guohua Zhong, and Gaopeng Song
College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China; Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou 510642, China.

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3O group or CF3O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation.

UI MeSH Term Description Entries
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014409 Tumor Necrosis Factor-alpha Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS. Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D044005 Tetrahydroisoquinolines A group of ISOQUINOLINES in which the nitrogen containing ring is protonated. They derive from the non-enzymatic Pictet-Spengler condensation of CATECHOLAMINES with ALDEHYDES. Tetrahydro-Isoquinoline,1,2,3,4-Tetrahydroisoquinolines,Tetrahydro-Isoquinolines,Tetrahydro Isoquinoline,Tetrahydro Isoquinolines
D054703 Cyclic Nucleotide Phosphodiesterases, Type 4 A cyclic nucleotide phosphodiesterase subfamily that is found predominantly in inflammatory cells and may play a role in the regulation of CELL-MEDIATED IMMUNITY. The enzyme family includes over twenty different variants that occur due to multiple ALTERNATIVE SPLICING of the mRNA of at least four different genes. Cyclic Nucleotide Phosphodiesterase PDE4 Family,Cyclic Nucleotide Phosphodiesterases, Type 4A,Cyclic Nucleotide Phosphodiesterases, Type 4A5,Cyclic Nucleotide Phosphodiesterases, Type 4B,Cyclic Nucleotide Phosphodiesterases, Type 4C,Cyclic Nucleotide Phosphodiesterases, Type 4D,Cyclic Nucleotide Phosphodiesterases, Type 4D3,PDE4 Phosphodiesterases,PDE4D3 Phosphodiesterase,Phosphodiesterase 4,Phosphodiesterase 4A,Phosphodiesterase 4B,Phosphodiesterase 4C,Phosphodiesterase 4D,Phosphodiesterase IV,Phosphodiesterase-4,Type 4 Cyclic Nucleotide Phosphodiesterase,cAMP-Specific Phosphodiesterase 4A5,Phosphodiesterase 4A5, cAMP-Specific,Phosphodiesterase, PDE4D3,Phosphodiesterases, PDE4,cAMP Specific Phosphodiesterase 4A5
D058988 Phosphodiesterase 4 Inhibitors Compounds that specifically inhibit PHOSPHODIESTERASE 4. PDE-4 Inhibitor,PDE4 Inhibitor,Phosphodiesterase 4 Inhibitor,Phosphodiesterase Type 4 Inhibitor,PDE-4 Inhibitors,PDE4 Inhibitors,Phosphodiesterase Type 4 Inhibitors,4 Inhibitor, Phosphodiesterase,Inhibitor, PDE-4,Inhibitor, PDE4,Inhibitor, Phosphodiesterase 4,Inhibitors, PDE-4,Inhibitors, PDE4,Inhibitors, Phosphodiesterase 4,PDE 4 Inhibitor,PDE 4 Inhibitors

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