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Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors. 2021

Bei Zhang, and Yue Huang, and Si-Rui Zhang, and Meng-Xing Huang, and Chen Zhang, and Hai-Bin Luo
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC50 of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t1/2 of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011744 Pyrimidinones Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. Pyrimidinone,Pyrimidone,Pyrimidones
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
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
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
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
D054677 Cyclic Nucleotide Phosphodiesterases, Type 1 A CALCIUM and CALMODULIN-dependent cyclic nucleotide phosphodiesterase subfamily. The three members of this family are referred to as type 1A, type 1B, and type 1C and are each product of a distinct gene. In addition, multiple enzyme variants of each subtype can be produced due to multiple alternative mRNA splicing. Although the type 1 enzymes are classified as 3',5'-cyclic-AMP phosphodiesterases (EC 3.1.4.17), some members of this class have additional specificity for CYCLIC GMP. Cyclic Nucleotide Phosphodiesterases, Type I,Ca(2+)-CaM-Stimulated PDE,Ca++ Calmodulin Dependent Cyclic AMP Phosphodiesterase,Ca-CaM-Phosphodiesterase,Calcium-Calmodulin-Dependent Phosphodiesterase,Calcium-Calmodulin-Stimulated Cyclic AMP Phosphodiesterase,Calmodulin Phosphodiesterase,Calmodulin-Dependent Phosphodiesterase,Calmodulin-Dependent cGMP Phosphodiesterase,Cyclic Nucleotide Phosphodiesterase PDE1 Family,Cyclic Nucleotide Phosphodiesterases, Type 1A,Cyclic Nucleotide Phosphodiesterases, Type 1B,Cyclic Nucleotide Phosphodiesterases, Type 1C,PDE1 Phosphodiesterases,Phosphodiesterase 1A, Calmodulin-Dependent,Phosphodiesterase 1B, Calmodulin-Dependent,Phosphodiesterase 1C, Calmodulin-Dependent,Ca CaM Phosphodiesterase,Calcium Calmodulin Dependent Phosphodiesterase,Calcium Calmodulin Stimulated Cyclic AMP Phosphodiesterase,Calmodulin Dependent Phosphodiesterase,Calmodulin Dependent cGMP Phosphodiesterase,Calmodulin-Dependent Phosphodiesterase 1A,Calmodulin-Dependent Phosphodiesterase 1B,Calmodulin-Dependent Phosphodiesterase 1C,Phosphodiesterase 1A, Calmodulin Dependent,Phosphodiesterase 1B, Calmodulin Dependent,Phosphodiesterase 1C, Calmodulin Dependent,Phosphodiesterase, Calcium-Calmodulin-Dependent,Phosphodiesterase, Calmodulin-Dependent cGMP,Phosphodiesterases, PDE1,cGMP Phosphodiesterase, Calmodulin-Dependent

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