Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation. 2015

Junhao Xing, and Lingyun Yang, and Hui Li, and Qing Li, and Leilei Zhao, and Xinning Wang, and Yuan Zhang, and Muxing Zhou, and Jinpei Zhou, and Huibin Zhang
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xingjhcpu@163.com.

The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 = 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.

UI MeSH Term Description Entries
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D011517 Prothrombin Time Clotting time of PLASMA recalcified in the presence of excess TISSUE THROMBOPLASTIN. Factors measured are FIBRINOGEN; PROTHROMBIN; FACTOR V; FACTOR VII; and FACTOR X. It is used for monitoring anticoagulant therapy with COUMARINS. Quick Test,Russell's Viper Venom Time,Thrombotest,Russell Viper Venom Time,Russells Viper Venom Time,Prothrombin Times,Test, Quick,Time, Prothrombin,Times, Prothrombin
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013918 Thrombin Time Clotting time of PLASMA mixed with a THROMBIN solution. It is a measure of the conversion of FIBRINOGEN to FIBRIN, which is prolonged by AFIBRINOGENEMIA, abnormal fibrinogen, or the presence of inhibitory substances, e.g., fibrin-fibrinogen degradation products, or HEPARIN. BATROXOBIN, a thrombin-like enzyme unaffected by the presence of heparin, may be used in place of thrombin. Reptilase Time,Reptilase Times,Thrombin Times,Time, Reptilase,Time, Thrombin,Times, Reptilase,Times, Thrombin
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
D015951 Factor Xa Activated form of factor X that participates in both the intrinsic and extrinsic pathways of blood coagulation. It catalyzes the conversion of prothrombin to thrombin in conjunction with other cofactors. Autoprothrombin C,Coagulation Factor Xa,Factor X, Activated,Thrombokinase,Activated Factor X,Blood Coagulation Factor X, Activated,Factor 10A,Factor Ten A,Factor Xa, Coagulation
D060326 Chemistry Techniques, Synthetic Methods used for the chemical synthesis of compounds. Included under this heading are laboratory methods used to synthesize a variety of chemicals and drugs. Inorganic Synthesis,Inorganic Synthesis Methods,Inorganic Synthesis Techniques,Methods of Inorganic Synthesis,Methods of Organic Synthesis,Methods of Peptide Synthesis,Organic Synthesis,Organic Synthesis Methods,Organic Synthesis Techniques,Peptide Synthesis Methods,Peptide Synthesis Techniques,Peptide Synthesis, Synthetic,Synthetic Chemistry Techniques,Synthetic Peptide Synthesis,Chemistry Technique, Synthetic,Inorganic Syntheses,Inorganic Synthesis Method,Inorganic Synthesis Technique,Method, Inorganic Synthesis,Method, Organic Synthesis,Method, Peptide Synthesis,Methods, Inorganic Synthesis,Methods, Organic Synthesis,Methods, Peptide Synthesis,Organic Syntheses,Organic Synthesis Technique,Peptide Syntheses, Synthetic,Peptide Synthesis Method,Peptide Synthesis Technique,Syntheses, Inorganic,Syntheses, Organic,Syntheses, Synthetic Peptide,Synthesis Method, Inorganic,Synthesis Method, Peptide,Synthesis Methods, Inorganic,Synthesis Methods, Peptide,Synthesis Technique, Inorganic,Synthesis Technique, Organic,Synthesis Technique, Peptide,Synthesis Techniques, Inorganic,Synthesis Techniques, Organic,Synthesis Techniques, Peptide,Synthesis, Inorganic,Synthesis, Organic,Synthesis, Synthetic Peptide,Synthetic Chemistry Technique,Synthetic Peptide Syntheses,Technique, Inorganic Synthesis,Technique, Organic Synthesis,Technique, Peptide Synthesis,Technique, Synthetic Chemistry,Techniques, Inorganic Synthesis,Techniques, Organic Synthesis,Techniques, Peptide Synthesis,Techniques, Synthetic Chemistry
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking
D062367 ortho-Aminobenzoates Benzoic acids, salts, or esters that contain an amino group attached to carbon number 2 or 6 of the benzene ring structure. 2-Aminobenzoates,6-Aminobenzoates,Anthranilates,Anthranilic Acids,o-Aminobenzoates,o-Aminobenzoic Acids,ortho-Aminobenzoic Acids,6 Aminobenzoates,Acids, Anthranilic,Acids, o-Aminobenzoic,Acids, ortho-Aminobenzoic,o Aminobenzoates,o Aminobenzoic Acids,ortho Aminobenzoates,ortho Aminobenzoic Acids
D065427 Factor Xa Inhibitors Endogenous factors and drugs that inhibit or block the activity of FACTOR XA. Direct Factor Xa Inhibitor,Direct-Acting Oral Anticoagulant,Direct-Acting Oral Anticoagulants,Factor Xa Inhibitor,Direct Factor Xa Inhibitors,Anticoagulant, Direct-Acting Oral,Anticoagulants, Direct-Acting Oral,Direct Acting Oral Anticoagulant,Direct Acting Oral Anticoagulants,Inhibitor, Factor Xa,Oral Anticoagulant, Direct-Acting,Oral Anticoagulants, Direct-Acting,Xa Inhibitor, Factor

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