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Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities. 2007

Ulrich Lücking, and Gerhard Siemeister, and Martina Schäfer, and Hans Briem, and Martin Krüger, and Philip Lienau, and Rolf Jautelat
Medicinal Chemistry, Research Center Europe, Schering AG, 13342 Berlin, Germany. ulrich.luecking@schering.de

X-ray structures from CDK2-aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late-stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF-RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000588 Amines A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed) Amine
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
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D018844 Cyclin-Dependent Kinases Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. Cyclin-Dependent Kinase,Cyclin-Dependent Protein Kinase,cdk Proteins,Cyclin-Dependent Protein Kinases,Cyclin Dependent Kinase,Cyclin Dependent Kinases,Cyclin Dependent Protein Kinase,Cyclin Dependent Protein Kinases,Kinase, Cyclin-Dependent,Kinase, Cyclin-Dependent Protein,Protein Kinase, Cyclin-Dependent
D023041 Xenograft Model Antitumor Assays In vivo methods of screening investigative anticancer drugs, biologic response modifiers or radiotherapies. Human tumor tissue or cells are transplanted into mice or rats followed by tumor treatment regimens. A variety of outcomes are monitored to assess antitumor effectiveness. Tumor Xenograft Assay,Xenograft Antitumor Assays,Antitumor Assays, Xenograft Model,Antitumor Assay, Xenograft,Antitumor Assays, Xenograft,Assay, Tumor Xenograft,Assay, Xenograft Antitumor,Assays, Tumor Xenograft,Assays, Xenograft Antitumor,Tumor Xenograft Assays,Xenograft Antitumor Assay,Xenograft Assay, Tumor,Xenograft Assays, Tumor
D040262 Receptors, Vascular Endothelial Growth Factor A family of closely related RECEPTOR PROTEIN-TYROSINE KINASES that bind vascular endothelial growth factors. They share a cluster of seven extracellular IG-LIKE DOMAINS which are important for ligand binding. They are highly expressed in vascular endothelial cells and are critical for the physiological and pathological growth, development and maintenance of blood and lymphatic vessels. Endothelial Growth Factor Receptor,Receptor, Endothelial Growth Factors,Receptor, Vascular Endothelial Cell Growth Factor,Receptor, Vascular Permeability Factor,VEGF Receptor,VEGF Receptors,VPF Receptor,Vascular Endothelial Cell Growth Factor Receptor,Vascular Endothelial Growth Factor Receptor,Vascular Permeability Factor Receptor,Receptors, VEGF

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