Abstract
A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Aurora Kinases
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Computational Biology
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HL-60 Cells
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Humans
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Male
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Mice
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Mice, SCID
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Models, Molecular
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Molecular Dynamics Simulation
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology*
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Transplantation, Heterologous
Substances
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3-(4-morpholin-4-yl-benzoylamino)-1H-thieno(3,2-c)pyrazole-5-carboxylic acid ((S)-1-phenyl-2-pyrrolidin-1-yl-ethyl)-amide
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Antineoplastic Agents
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Enzyme Inhibitors
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Pyrazoles
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Thiophenes
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Aurora Kinases
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Protein Serine-Threonine Kinases